C7 substituted oxysterols and methods of use thereof

ABSTRACT

Compounds are provided according to Formula (A):and pharmaceutically acceptable salts thereof, and pharmaceutical compositions thereof; wherein R1A, R1B, n, R2A, R2B, R3, and R4 are as defined herein. Compounds of the present invention are contemplated useful for the prevention and treatment of a variety of conditions.

RELATED APPLICATIONS

This application is a divisional of U.S. patent application Ser. No.16/338,315, filed Mar. 29, 2019, which is a U.S. National PhaseApplication under 35 U.S.C. § 371 of International ApplicationPCT/US2017/054657, filed Sep. 30, 2017, which claims priority to and thebenefit of U.S. Provisional Application No. 62/402,789, filed Sep. 30,2016, and U.S. Provisional Application No. 62/402,797, filed Sep. 30,2016. The disclosures of each of the foregoing applications areincorporated herein by reference in their entirety.

BACKGROUND OF THE INVENTION

NMDA receptors are heteromeric complexes comprised of NR1, NR2, and/orNR3 subunits and possess distinct recognition sites for exogenous andendogenous ligands. These recognition sites include binding sites forglycine, and glutamate agonists and modulators. NMDA receptors areexpressed in the peripheral tissues and the CNS, where they are involvedin excitatory synaptic transmission. Activating these receptorscontributes to synaptic plasticity in some circumstances andexcitotoxicity in others. These receptors are ligand-gated ion channelsthat admit Ca²⁺ after binding of the glutamate and glycine, and arefundamental to excitatory neurotransmission and normal CNS function.Positive modulators may be useful as therapeutic agents with potentialclinical uses as cognitive enhancers and in the treatment of psychiatricdisorders in which glutamatergic transmission is reduced or defective(see, e.g., Horak et al., J. of Neuroscience, 2004, 24(46),10318-10325). In contrast, negative modulators may be useful astherapeutic agents with potential clinical uses in the treatment ofpsychiatric disorders in which glutamatergic transmission ispathologically increased (e.g., treatment resistant depression).

Oxysterols are cholesterol analogs that are modulators of NMDA receptorfunction. There is a need for new oxysterols that modulate the NMDAreceptor for the prevention and treatment of conditions associated withNMDA expression and function. Compounds, compositions, and methodsdescribed herein are directed toward this end.

SUMMARY OF THE INVENTION

Provided herein are substituted oxysterols useful for preventing and/ortreating a broad range of disorders, including, but not limited to,NMDA-mediated disorders. Further provided are pharmaceuticalcompositions comprising the compounds of the present invention, andmethods of their use and treatment.

In one aspect, provided herein are compounds according to Formula (A):

or a pharmaceutically acceptable salt thereof, wherein:

each of R^(1A) and R^(1B) is independently hydrogen, substituted orunsubstituted alkyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl, orR^(1A) and R^(1B), together with the carbon atom to which they areattached form a 3-8 membered ring;

n is 1 or 2;

each of R^(2A) and R^(2B) is independently hydrogen, halo, —OR^(C),alkyl, alkenyl, alkynyl, aryl, or heteroaryl, wherein R^(C) is hydrogenor alkyl, or R^(2A) and R^(2B), together with the carbon atom to whichthey are attached form an oxo group, wherein R^(2A) and R^(2B) are notboth simultaneously hydrogen;

R³ is hydrogen, alkyl, alkenyl, alkynyl, or —OR^(A), wherein R^(A) isalkyl;

R⁴ is absent or hydrogen; and

represents a single or double bond, wherein when one of

is a double bond, the other

is a single bond; when both of

are single bonds, then R⁴ is hydrogen; and when one of the

is a double bond, R⁴ is absent.

In some embodiments, n is 1. In other embodiments, n is 2.

In some embodiments, when R^(1A), R³, and R⁴ are hydrogen and R^(1B) isunsubstituted isopropyl, then R^(2A) and R^(2B), together with thecarbon atom to which they are attached do not form an oxo group; andwhen R⁴ is absent, R³ is hydrogen, and R^(1A) and R^(1B) are —CH₃, thenR^(2A) is not —CH₃ and R^(2B) is not —OH. In further embodiments, n is1.

In some embodiments, when R⁴ is absent, R^(2A) is —OH, R^(2B) ishydrogen or —CF₃, and R^(1A) and R^(1B) are —CH₃, then R³ is nothydrogen; and when R^(1A) and R^(1B) are —CH₃ and R³ is hydrogen, thenR^(2A) and R^(2B), together with the carbon atom to which they areattached do not form an oxo group. In further embodiments, n is 2.

In some embodiments, wherein the compound of Formula (A) is a compoundof Formula (A-I):

In some embodiments, the compound of Formula (A) is a compound ofFormula (A-II):

In some embodiments, the compound of Formula (A) is a compound ofFormula (A-III):

In some embodiments, the compound of Formula (A) is a compound ofFormula (A-IV), (A-V), or (A-VI):

wherein R^(2C) is hydrogen or alkyl and R³ is alkyl, alkenyl, alkynyl,or —OR^(A), wherein R^(A) is alkyl.

In some embodiments, the compound of Formula (A) is a compound ofFormula (A-VII), (A-VIII), or (A-IX):

wherein R³ is alkyl, alkenyl, alkynyl, or —OR^(A), wherein R^(A) isalkyl.

In some embodiments, the compound of Formula (A) is a compound ofFormula (A-X):

wherein R³ is alkyl, alkenyl, alkynyl, or —OR^(A), wherein R^(A) isalkyl.

In some embodiments, the compound of Formula (A) is a compound ofFormula (A-XII)

where R′ is alkyl or —OR^(A), wherein R^(A) is hydrogen or alkyl; p is0, 1, 2, 3, 4, 5, or 6; and m is 0, 1, 2, or 3.

In some embodiments, R⁴ is absent, one of R^(2A) and R^(2B) is —OH, andR³ is not hydrogen.

In some embodiments, each of R^(1A) and R^(1B) is independentlyunsubstituted or substituted alkyl (e.g., haloalkyl, alkoxyalkyl, —CH₃,—CH₂CH₃, —CH(CH₃)₂, —CF₃ or —CH₂OCH₃).

In other embodiments, each of R^(1A) and R^(1B) is independentlysubstituted alkyl (e.g., haloalkyl). In some embodiments, R^(1A) andR^(1B) is alkyl (e.g., unsubstituted or substituted alkyl (e.g., —CH₃)).In some embodiments, R^(1A) and R^(1B) are —CH₃.

In some aspects, R^(1A) is —CF₃ or —CH₂OCH₃.

In other aspects, R^(1A) is hydrogen and R^(1B) is alkyl, carbocyclyl,heterocyclyl, aryl, or heteroaryl.

In some embodiments, R^(1A) and R^(1B), together with the carbon atom towhich they are attached form a 3-8 membered ring.

In some aspects, R^(1A) is substituted alkyl or unsubstituted C₂-C₆alkyl and R^(1B) is substituted or unsubstituted C₁-C₆ alkyl.

In some embodiments, each of R^(2A) and R^(2B) is independently alkyl(e.g., substituted or unsubstituted alkyl). In some aspects, each ofR^(2A) and R^(2B) is independently —F.

In other embodiments, R^(2A) and R^(2B) are —CH₃ and R³ is alkyl,alkenyl, alkynyl, or —OR^(A), wherein R^(A) is alkyl. In some otherembodiments, each of R^(2A) and R^(2B) is independently hydrogen and R³is alkyl (e.g., substituted or unsubstituted alkyl).

In some embodiments, wherein R³ is alkyl (e.g., substituted orunsubstituted alkyl), alkenyl, alkynyl, or —OR^(A), wherein R^(A) isalkyl. In other embodiments, R³ is alkyl (e.g., substituted orunsubstituted alkyl).

In one aspect, provided herein are compounds according to Formula (B):

or a pharmaceutically acceptable salt thereof, wherein:

each of R^(1A) and R^(1B) is independently hydrogen, substituted orunsubstituted alkyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl, orR^(1A) and R^(1B), together with the carbon atom to which they areattached form a 3-8 membered ring;

n is 1 or 2;

each of R^(2A) and R^(2B) is independently hydrogen, halo, —OR^(C),alkyl, alkenyl, alkynyl, aryl, or heteroaryl, wherein R^(C) is hydrogenor alkyl, or R^(2A) and R^(2B), together with the carbon atom to whichthey are attached form an oxo group, wherein R^(2A) and R^(2B) are notboth simultaneously hydrogen;

R³ is alkyl, alkenyl, alkynyl, or —OR^(A), wherein R^(A) is alkyl;

R⁴ is absent or hydrogen; and

represents a single or double bond, wherein when one of

is a double bond, the other

is a single bond; when both of

are single bonds, then R⁴ is hydrogen; and when one of the

is a double bond, R⁴ is absent.

In some embodiments, n is 1. In other embodiments, n is 2.

In some embodiments, wherein the compound of Formula (B) is a compoundof Formula (B-I):

In some embodiments, the compound of Formula (B) is a compound ofFormula (B-II):

In some embodiments, the compound of Formula (B) is a compound ofFormula (B-III):

In some embodiments, the compound of Formula (B) is a compound ofFormula (B-IV), (B-V), or (B-VI):

wherein R^(2C) is hydrogen or alkyl and R³ is alkyl, alkenyl, alkynyl,or —OR^(A), wherein R^(A) is alkyl.

In some embodiments, the compound of Formula (B) is a compound ofFormula (B-VII), (B-VIII), or (B-IX):

wherein R³ is alkyl, alkenyl, alkynyl, or —OR^(A), wherein R^(A) isalkyl.

In some embodiments, the compound of Formula (B) is a compound ofFormula (B-X):

wherein R³ is alkyl, alkenyl, alkynyl, or —OR^(A), wherein R^(A) isalkyl.

In some embodiments, the compound of Formula (B) is a compound ofFormula (B-XII)

where R′ is alkyl or —OR^(A), wherein R^(A) is hydrogen or alkyl; p is0, 1, 2, 3, 4, 5, or 6; and m is 0, 1, 2, or 3.

In some embodiments, each of R^(1A) and R^(1B) is independentlyunsubstituted or substituted alkyl (e.g., haloalkyl, alkoxyalkyl, —CH₃,—CH₂CH₃, —CH(CH₃)₂, —CF₃ or —CH₂OCH₃).

In other embodiments, each of R^(1A) and R^(1B) is independentlysubstituted alkyl (e.g., haloalkyl). In some embodiments, R^(1A) andR^(1B) is alkyl (e.g., unsubstituted or substituted alkyl (e.g., —CH₃)).In some embodiments, R^(1A) and R^(1B) are —CH₃.

In some aspects, R^(1A) is —CF₃ or —CH₂OCH₃.

In other aspects, R^(1A) is hydrogen and R^(1B) is alkyl, carbocyclyl,heterocyclyl, aryl, or heteroaryl.

In some embodiments, R^(1A) and R^(1B), together with the carbon atom towhich they are attached form a 3-8 membered ring.

In some aspects, R^(1A) is substituted alkyl or unsubstituted C₂-C₆alkyl and R^(1B) is substituted or unsubstituted C₁-C₆ alkyl.

In some embodiments, each of R^(2A) and R^(2B) is independently alkyl(e.g., substituted or unsubstituted alkyl). In some aspects, each ofR^(2A) and R^(2B) is independently —F.

In other embodiments, R^(2A) and R^(2B) are —CH₃ and R³ is alkyl,alkenyl, alkynyl, or —OR^(A), wherein R^(A) is alkyl. In some otherembodiments, each of R^(2A) and R^(2B) is independently hydrogen and R³is alkyl (e.g., substituted or unsubstituted alkyl).

In some embodiments, wherein R³ is alkyl (e.g., substituted orunsubstituted alkyl), alkenyl, alkynyl, or —OR^(A), wherein R^(A) isalkyl. In other embodiments, R³ is alkyl (e.g., substituted orunsubstituted alkyl).

In one aspect, provided herein are compounds according to Formula (I):

or a pharmaceutically acceptable salt thereof, wherein:

each of R^(1A) and R^(1B) is independently hydrogen, substituted orunsubstituted alkyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl, orR^(1A) and R^(1B), together with the carbon atom to which they areattached form a 3-8 membered ring;

each of R^(2A) and R^(2B) is independently hydrogen, halo, —OR^(C),alkyl, alkenyl, alkynyl, aryl, or heteroaryl, wherein R^(C) is hydrogenor alkyl, or R^(2A) and R^(2B), together with the carbon atom to whichthey are attached form an oxo group, wherein R^(2A) and R^(2B) are notboth simultaneously hydrogen;

R³ is hydrogen, alkyl, alkenyl, alkynyl, or —OR^(A), wherein R^(A) isalkyl;

R⁴ is absent or hydrogen; and

represents a single or double bond, wherein when one of

is a double bond, the other

is a single bond; when both of

are single bonds, then R⁴ is hydrogen; and when one of the

is a double bond, R⁴ is absent;

wherein when R^(1A), R³, and R⁴ are hydrogen and R^(1B) is unsubstitutedisopropyl, then R^(2A) and R^(2B), together with the carbon atom towhich they are attached do not form an oxo group; and

when R⁴ is absent, R³ is hydrogen, and R^(1A) and R^(1B) are —CH₃, thenR^(2A) is not —CH₃ and R^(2B) is not —OH.

In some embodiments, R^(1A), R³, and R⁴ are hydrogen, R^(1B) isunsubstituted isopropyl, and R^(2A) and R^(2B), together with the carbonatom to which they are attached do not form an oxo group.

In some embodiments, R⁴ is absent, R³ is hydrogen, R^(1A) and R^(1B) are—CH₃, R^(2A) is not —CH₃, and R^(2B) is not —OH.

In some embodiments, wherein the compound of Formula (I) is a compoundof Formula (I-A):

In some embodiments, the compound of Formula (I) is a compound ofFormula (I-B):

In some embodiments, the compound of Formula (I) is a compound ofFormula (I-C):

In some embodiments, the compound of Formula (I) is a compound ofFormula (I-E), (I-F), or (I-G):

wherein R^(2C) is hydrogen or alkyl and R³ is alkyl, alkenyl, alkynyl,or —OR^(A), wherein R^(A) is alkyl.

In some embodiments, the compound of Formula (I) is a compound ofFormula (I-H), (I-I), or (I-J):

wherein R³ is alkyl, alkenyl, alkynyl, or —OR^(A), wherein R^(A) isalkyl.

In some embodiments, the compound of Formula (I) is a compound ofFormula (I-K):

wherein R³ is alkyl, alkenyl, alkynyl, or —OR^(A), wherein R^(A) isalkyl.

In some embodiments, the compound of Formula (I) is a compound ofFormula (I-M):

where R′ is alkyl or —OR^(A), wherein R^(A) is hydrogen or alkyl; p is0, 1, 2, 3, 4, 5, or 6; and m is 0, 1, 2, or 3.

In some embodiments, each of R^(1A) and R^(1B) is independentlyunsubstituted or substituted alkyl (e.g., haloalkyl, alkoxyalkyl, —CH₃,—CH₂CH₃, —CH(CH₃)₂, —CF₃ or —CH₂OCH₃).

In some embodiments, each of R^(1A) and R^(1B) is independentlysubstituted alkyl (e.g., haloalkyl).

In some embodiments, R^(1A) is —CF₃ or —CH₂OCH₃.

In some embodiments, R^(1A) and R^(1B) is alkyl (e.g., unsubstituted orsubstituted alkyl (e.g., —CH₃)).

In some embodiments, R^(1A) and R^(1B) are —CH₃.

In some embodiments, R^(1A) and R^(1B), together with the carbon atom towhich they are attached form a 3-8 membered ring.

In some embodiments, R^(1A) is hydrogen and R^(1B) is alkyl,carbocyclyl, heterocyclyl, aryl, or heteroaryl.

In some embodiments, R^(1A) is substituted alkyl or unsubstituted C₂-C₆alkyl and R^(1B) is substituted or unsubstituted C₁-C₆ alkyl.

In some embodiments, each of R^(2A) and R^(2B) is independently alkyl(e.g., substituted or unsubstituted alkyl).

In some embodiments, each of R^(2A) and R^(2B) is independently —F.

In some embodiments, R^(2A) and R^(2B) are —CH₃ and R³ is alkyl,alkenyl, alkynyl, or —OR^(A), wherein R^(A) is alkyl.

In some embodiments, R^(2A) and R^(2B) are —F.

In some embodiments, R³ is alkyl (e.g., substituted or unsubstitutedalkyl), alkenyl, alkynyl, or —OR^(A), wherein R^(A) is alkyl.

In some embodiments, R³ is alkyl (e.g., substituted or unsubstitutedalkyl).

In some embodiments, each of R^(2A) and R^(2B) is independently hydrogenand R³ is alkyl (e.g., substituted or unsubstituted alkyl).

In one aspect, provided herein are compounds according to Formula (II):

or a pharmaceutically acceptable salt thereof, wherein:

each of R^(1A) and R^(1B) is independently hydrogen, substituted orunsubstituted alkyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl, orR^(1A) and R^(1B), together with the carbon atom to which they areattached form a 3-8 membered ring;

each of R^(2A) and R^(2B) is independently hydrogen, halo, —OR^(C),alkyl, alkenyl, alkynyl, aryl, or heteroaryl, wherein R^(C) is hydrogenor alkyl, or R^(2A) and R^(2B), together with the carbon atom to whichthey are attached form an oxo group, wherein R^(2A) and R^(2B) are notboth simultaneously hydrogen;

R³ is hydrogen, alkyl, alkenyl, alkynyl, or —OR^(A), wherein

R^(A) is alkyl;

R⁴ is absent or hydrogen; and

represents a single or double bond, wherein when one of

is a double bond, the other

is a single bond; when both of

are single bonds, then R⁴ is hydrogen; and when one of the

is a double bond, R⁴ is absent;

provided that when R⁴ is absent, R^(2A) is —OH, R^(2B) is hydrogen or—CF₃, and R^(1A) and R^(1B) are —CH₃, then R³ is not hydrogen; and

when R^(1A) and R^(1B) are —CH₃ and R³ is hydrogen, then R^(2A) andR^(2B), together with the carbon atom to which they are attached do notform an oxo group.

In some embodiments, R⁴ is absent, one of R^(2A) and R^(2B) is —OH, andR³ is not hydrogen.

In some embodiments, the compound of Formula (II) is a compound ofFormula (II-A):

In some embodiments, the compound of Formula (II) is a compound ofFormula (II-B):

In some embodiments, the compound of Formula (II) is a compound ofFormula (II-C):

In some embodiments, the compound of Formula (II) is a compound ofFormula (II-D):

In some embodiments, the compound of Formula (II) is a compound ofFormula (II-E), (II-F), or (II-G):

wherein R^(2C) is hydrogen or alkyl (e.g., substituted or unsubstitutedalkyl) and R³ is alkyl (e.g., substituted or unsubstituted alkyl).

In some embodiments, the compound of Formula (II) is a compound ofFormula (II-H), (II-I), or (II-J):

wherein R³ is alkyl, alkenyl, alkynyl, or —OR^(A), wherein R^(A) isalkyl.

In some embodiments, the compound of Formula (II) is a compound ofFormula (II-K):

where R′ is alkyl or —OR^(A), wherein R^(A) is hydrogen or alkyl; p is0, 1, 2, 3, 4, 5, or 6; and m is 0, 1, 2, or 3.

In some embodiments, each of R^(1A) and R^(1B) is independentlyunsubstituted or substituted alkyl (e.g., haloalkyl, alkoxyalkyl, —CH₃,—CH₂CH₃, —CH(CH₃)₂, CF₃ or —CH₂OCH₃).

In some embodiments, each of R^(1A) and R^(1B) is independentlysubstituted alkyl (e.g., haloalkyl).

In some embodiments, R^(1A) is —CF₃ or —CH₂OCH₃.

In some embodiments, R^(1A) and R^(1B) is alkyl (e.g., unsubstituted orsubstituted alkyl (e.g., —CH₃)).

In some embodiments, R^(1A) and R^(1B) are —CH₃.

In some embodiments, R^(1A) and R^(1B), together with the carbon atom towhich they are attached form a ring.

In some embodiments, R^(1A) is hydrogen and R^(1B) is alkyl,carbocyclyl, heterocyclyl, aryl, or heteroaryl.

In some embodiments, each of R^(2A) and R^(2B) is independently alkyl(e.g., substituted or unsubstituted alkyl).

In some embodiments, R³ is alkyl (e.g., substituted or unsubstitutedalkyl).

In some embodiments, each of R^(2A) and R^(2B) is independently hydrogenand R³ is alkyl (e.g., substituted or unsubstituted alkyl).

In some embodiments, each of R^(2A) and R^(2B) is independently —F.

In some embodiments, R^(2A) and R^(2B) are —CH₃ and R³ is alkyl,alkenyl, alkynyl, or —OR^(A), wherein R^(A) is alkyl.

In some embodiments, R^(2A) and R^(2B) are —F.

In some embodiments, R^(1A) is substituted alkyl or unsubstituted C₂-C₆alkyl and R^(1B) is substituted or unsubstituted C₁-C₆ alkyl.

In some aspects, the compound is a compound of Formula (III):

or a pharmaceutically acceptable salt thereof, wherein:

each of R^(1A) and R^(1B) is substituted or unsubstituted alkyl;

each of R^(2A) and R^(2B) is independently hydrogen, —OR^(C), or alkyl,wherein R^(C) is hydrogen or alkyl, or

R^(2A) and R^(2B), together with the carbon atom to which they areattached form an oxo group, wherein R^(2A) and R^(2B) are not bothsimultaneously hydrogen;

R³ is alkyl;

R⁴ is absent or hydrogen; and

represents a single or double bond, wherein when one of

is a double bond, the other

is a single bond; when both of

are single bonds, then R⁴ is hydrogen; and when one of the

is a double bond, R⁴ is absent.

In some embodiments, R^(1A) and R^(1B) are each —CH₃.

In some embodiments, R^(2A) and R^(2B) together with the carbon atom towhich they are attached form an oxo group.

In some embodiments, R³ is —CH₂CH₃.

In some embodiments, R^(2A) is —OH and R^(2B) is H.

In some embodiments, R^(2A) is —CH₃ and R^(2B) is H.

In some embodiments, R^(2A) is —OH and R^(2B) is —CH₃.

In some embodiments, R^(1A) is —CF₃.

In an aspect, provided herein is a pharmaceutical composition comprisinga compound described herein, or pharmaceutically acceptable saltthereof, and a pharmaceutically acceptable carrier.

In an aspect, provided herein is a method of inducing sedation oranesthesia comprising administering to a subject an effective amount ofa compound described herein, or pharmaceutically acceptable saltthereof, or pharmaceutical composition thereof.

In an aspect, provided herein is a method for treating or preventing adisorder described herein, comprising administering to a subject in needthereof an effective amount of a compound described herein, orpharmaceutically acceptable salt thereof, or pharmaceutical compositionthereof.

In some embodiments, the disorder is an autoimmune disorder.

In some embodiments, the disorder is rheumatoid arthritis, juvenileidiopathic arthritis, ankylosing spondylitis, psoriatic arthritis,Crohn's disease, ulcerative colitis, and plaque psoriasis.

In some embodiments, the disorder is a metabolic disorder.

In some embodiments, the disorder is a gastrointestinal (GI) disordere.g., constipation, irritable bowel syndrome (IBS), inflammatory boweldisease (IBD) (e.g., ulcerative colitis, Crohn's disease), structuraldisorders affecting the GI, anal disorders (e.g., hemorrhoids, internalhemorrhoids, external hemorrhoids, anal fissures, perianal abscesses,anal fistula), colon polyps, cancer, or colitis.

In some embodiments, the disorder is inflammatory bowel disease.

In some embodiments, the disorder is cancer, diabetes, or a sterolsynthesis disorder.

In an aspect, provided herein is a method for treating or preventing aCNS-related condition comprising administering to a subject in needthereof an effective amount of a compound described herein, orpharmaceutically acceptable salt thereof, or pharmaceutical compositionthereof. In some embodiments, the CNS-related condition is an adjustmentdisorder, anxiety disorder (including obsessive-compulsive disorder,posttraumatic stress disorder, and social phobia), cognitive disorder(including Alzheimer's disease and other forms of dementia (e.g.,frontotemporal dementia), dissociative disorder, eating disorder, mooddisorder (including depression (e.g., postpartum depression), bipolardisorder, dysthymic disorder, suicidality), schizophrenia or otherpsychotic disorder (including schizoaffective disorder), sleep disorder(including insomnia), substance-related disorder, personality disorder(including obsessive-compulsive personality disorder), autism spectrumdisorders (including those involving mutations to the Shank group ofproteins (e.g., Shank3)), neurodevelopmental disorder (including Rettsyndrome, Tuberous Sclerosis complex), multiple sclerosis, sterolsynthesis disorders, pain (including acute and chronic pain; headaches,e.g., migraine headaches), encephalopathy secondary to a medicalcondition (including hepatic encephalopathy and anti-NMDA receptorencephalitis), seizure disorder (including status epilepticus andmonogenic forms of epilepsy such as Dravet's disease), stroke, traumaticbrain injury, movement disorder (including Huntington's disease andParkinson's disease), vision impairment, hearing loss, or tinnitus.

In some embodiments, the disorder is Huntington's disease. In someembodiments, the disorder is Parkinson's disease. In some embodiments,the disorder is an inflammatory disease (e.g., lupus).

In some embodiments, the disorder is a sterol synthesis disorder.

In some embodiments, the disorder is Smith-Lemli-Opitz Syndrome (SLOS).In some embodiments, the disorder is desmosterolosis. In someembodiments, the disorder is sitosterolemia. In some embodiments, thedisorder is cerebrotendinous xanthomatosis (CTX). In some embodiments,the disorder is Mevalonate Kinase Deficiency (MKD). In some embodiments,the disorder is SC4MOL gene mutation (SMO Deficiency). In someembodiments, the disorder is Niemann-Pick disease. In some embodiments,the disorder is autism spectrum disorder (ASD). In some embodiments, thedisorder is associated with phenylketomuria.

Other objects and advantages will become apparent to those skilled inthe art from a consideration of the ensuing Detailed Description,Examples, and Claims.

Definitions Chemical Definitions

Definitions of specific functional groups and chemical terms aredescribed in more detail below. The chemical elements are identified inaccordance with the Periodic Table of the Elements, CAS version,Handbook of Chemistry and Physics, 75^(th) Ed., inside cover, andspecific functional groups are generally defined as described therein.Additionally, general principles of organic chemistry, as well asspecific functional moieties and reactivity, are described in ThomasSorrell, Organic Chemistry, University Science Books, Sausalito, 1999;Smith and March, March's Advanced Organic Chemistry, 5^(th) Edition,John Wiley & Sons, Inc., New York, 2001; Larock, Comprehensive OrganicTransformations, VCH Publishers, Inc., New York, 1989; and Carruthers,Some Modern Methods of Organic Synthesis, 3r^(d) Edition, CambridgeUniversity Press, Cambridge, 1987.

Isomers can be isolated from mixtures by methods known to those skilledin the art, including chiral high pressure liquid chromatography (HPLC)and the formation and crystallization of chiral salts; or preferredisomers can be prepared by asymmetric syntheses. See, for example,Jacques et al., Enantiomers, Racemates and Resolutions (WileyInterscience, New York, 1981); Wilen et al., Tetrahedron 33:2725 (1977);Eliel, Stereochemistry of Carbon Compounds (McGrawHill, NY, 1962); andWilen, Tables of Resolving Agents and Optical Resolutions p. 268 (E.L.Eliel, Ed., Univ. of Notre Dame Press, Notre Dame, Ind. 1972). Theinvention additionally encompasses compounds described herein asindividual isomers substantially free of other isomers, andalternatively, as mixtures of various isomers.

The “enantiomeric excess” (“e.e.”) or “% enantiomeric excess” (“%e.e.”)of a composition refers to an excess of one enantiomer relative to theother enantiomer present in the composition. For example, a compositioncan contain 90% of one enantiomer, e.g., the S enantiomer, and 10% ofthe other enantiomer, i.e., the R enantiomer.

e.e. =(90−10)/100=80%.

Thus, a composition containing 90% of one enantiomer and 10% of theother enantiomer is said to have an enantiomeric excess of 80%.

The “diastereomeric excess” (“d.e.”) or “% diastereomeric excess”(“%d.e.”) of a composition refers to an excess of one diastereomerrelative to one or more different diasteromers present in thecomposition. For example, a composition can contain 90% of onediastereomer, and 10% of one or more different diastereomers.

d.e.=(90−10)/100=80%.

Thus, a composition containing 90% of one diastereomers and 10% of oneor more different diastereomers is said to have a diastereomeric excessof 80%.

When a range of values is listed, it is intended to encompass each valueand sub-range within the range. For example “C₁₋₆ alkyl” is intended toencompass, C₁, C₂, C₃, C₄, C₅, C₆, C₁₋₆, C₁₋₅, C₁₋₄, C₁₋₃, C₁₋₂, C₂₋₆,C₂₋₅, C₂₋₄, C₂₋₃, C₃₋₆, C₃₋₅, C₃₋₄, C₄₋₆, C₄₋₅, and C₅₋₆ alkyl.

The following terms are intended to have the meanings presentedtherewith below and are useful in understanding the description andintended scope of the present invention.

When describing the invention, which may include compounds,pharmaceutical compositions containing such compounds and methods ofusing such compounds and compositions, the following terms, if present,have the following meanings unless otherwise indicated. It should alsobe understood that when described herein any of the moieties definedforth below may be substituted with a variety of substituents, and thatthe respective definitions are intended to include such substitutedmoieties within their scope as set out below. Unless otherwise stated,the term “substituted” is to be defined as set out below. It should befurther understood that the terms “groups” and “radicals” can beconsidered interchangeable when used herein. The articles “a” and “an”may be used herein to refer to one or to more than one (i.e. at leastone) of the grammatical objects of the article. By way of example “ananalogue” means one analogue or more than one analogue.

“Aliphatic” refers to an alkyl, alkenyl, alkynyl, or carbocyclyl group,as defined herein.

“Alkyl” refers to a radical of a straightchain or branched saturatedhydrocarbon group having from 1 to 20 carbon atoms (“C₁₋₂₀ alkyl”). Insome embodiments, an alkyl group has 1 to 12 carbon atoms (“C₁₋₁₂alkyl”). In some embodiments, an alkyl group has 1 to 10 carbon atoms(“C₁₋₁₀ alkyl”). In some embodiments, an alkyl group has 1 to 9 carbonatoms (“C₁₋₉ alkyl”). In some embodiments, an alkyl group has 1 to 8carbon atoms (“C₁₋₈ alkyl”). In some embodiments, an alkyl group has 1to 7 carbon atoms (“C₁₋₇ alkyl”). In some embodiments, an alkyl grouphas 1 to 6 carbon atoms (“C₁₋₆ alkyl”, also referred to herein as “loweralkyl”). In some embodiments, an alkyl group has 1 to 5 carbon atoms(“C₁₋₅ alkyl”). In some embodiments, an alkyl group has 1 to 4 carbonatoms (“C₁₋₄ alkyl”). In some embodiments, an alkyl group has 1 to 3carbon atoms (“C₁₋₃ alkyl”). In some embodiments, an alkyl group has 1to 2 carbon atoms (“C₁₋₂ alkyl”). In some embodiments, an alkyl grouphas 1 carbon atom (“C₁ alkyl”). In some embodiments, an alkyl group has2 to 6 carbon atoms (“C₂₋₆ alkyl”). Examples of C₁₋₆ alkyl groupsinclude methyl (C₁), ethyl (C₂), n-propyl (C₃), isopropyl (C₃), n-butyl(C₄), tert-butyl (C₄), sec-butyl (C₄), iso-butyl (C₄), n-pentyl (C₅),3-pentanyl (C₅), amyl (C₅), neopentyl (C₅), 3methyl-2-butanyl (C₅),tertiary amyl (C₅), and n-hexyl (C₆). Additional examples of alkylgroups include n-heptyl (C₇), n-octyl (C₈) and the like. Unlessotherwise specified, each instance of an alkyl group is independentlyoptionally substituted, i.e., unsubstituted (an “unsubstituted alkyl”)or substituted (a “substituted alkyl”) with one or more substituents;e.g., for instance from 1 to 5 substituents, 1 to 3 substituents, or 1substituent. In certain embodiments, the alkyl group is unsubstitutedC₁₋₁₀ alkyl (e.g., —CH₃). In certain embodiments, the alkyl group issubstituted C₁₋₁₀ alkyl. Common alkyl abbreviations include Me (—CH₃),Et (—CH₂CH₃), iPr (—CH(CH₃)₂), nPr (—CH₂CH₂CH₃), n-Bu (—CH₂CH₂CH₂CH₃),or i-Bu (—CH₂CH(CH₃)₂).

“Alkylene” refers to an alkyl group wherein two hydrogens are removed toprovide a divalent radical, and which may be substituted orunsubstituted. Unsubstituted alkylene groups include, but are notlimited to, methylene (—CH₂—), ethylene (—CH₂CH₂—), propylene(—CH₂CH₂CH₂—), butylene (—CH₂CH₂CH₂CH₂—), pentylene (—CH₂CH₂CH₂CH₂CH₂—),hexylene (—CH₂CH₂CH₂CH₂CH₂CH₂—), and the like. Exemplary substitutedalkylene groups, e.g., substituted with one or more alkyl (methyl)groups, include but are not limited to, substituted methylene(—CH(CH₃)—, (—C(CH₃)₂—), substituted ethylene (—CH(CH₃)CH₂—,—CH₂CH(CH₃)—, —C(CH₃)₂CH₂—, —CH₂C(CH₃)₂—), substituted propylene(—CH(CH₃)CH₂CH₂—, —CH₂CH(CH₃)CH₂—, —CH₂CH₂CH(CH₃)—, —C(CH₃)₂CH₂CH₂—,—CH₂C(CH₃)₂CH₂—, —CH₂CH₂C(CH₃)₂—), and the like. When a range or numberof carbons is provided for a particular alkylene group, it is understoodthat the range or number refers to the range or number of carbons in thelinear carbon divalent chain. Alkylene groups may be substituted orunsubstituted with one or more substituents as described herein.

“Alkenyl” refers to a radical of a straight-chain or branchedhydrocarbon group having from 2 to 20 carbon atoms, one or morecarbon-carbon double bonds (e.g., 1, 2, 3, or 4 carbon-carbon doublebonds), and optionally one or more carbon-carbon triple bonds (e.g., 1,2, 3, or 4 carbon-carbon triple bonds) (“C₂₋₂₀ alkenyl”). In certainembodiments, alkenyl does not contain any triple bonds. In someembodiments, an alkenyl group has 2 to 10 carbon atoms (“C₂₋₁₀alkenyl”). In some embodiments, an alkenyl group has 2 to 9 carbon atoms(“C₂₋₉ alkenyl”).

In some embodiments, an alkenyl group has 2 to 8 carbon atoms (“C₂₋₈alkenyl”). In some embodiments, an alkenyl group has 2 to 7 carbon atoms(“C₂₋₇ alkenyl”). In some embodiments, an alkenyl group has 2 to 6carbon atoms (“C₂₋₆ alkenyl”). In some embodiments, an alkenyl group has2 to 5 carbon atoms (“C₂₋₅ alkenyl”). In some embodiments, an alkenylgroup has 2 to 4 carbon atoms (“C₂₋₄ alkenyl”). In some embodiments, analkenyl group has 2 to 3 carbon atoms (“C₂₋₃ alkenyl”). In someembodiments, an alkenyl group has 2 carbon atoms (“C₂ alkenyl”). The oneor more carbon-carbon double bonds can be internal (such as in2-butenyl) or terminal (such as in 1-butenyl). Examples of C₂₋₄ alkenylgroups include ethenyl (C₂), 1-propenyl (C₃), 2-propenyl (C₃), 1-butenyl(C₄), 2-butenyl (C₄), butadienyl (C₄), and the like. Examples of C₂₋₆alkenyl groups include the aforementioned C₂₋₄ alkenyl groups as well aspentenyl (C₅), pentadienyl (C₅), hexenyl (C₆), and the like. Additionalexamples of alkenyl include heptenyl (C₇), octenyl (C₈), octatrienyl(C₈), and the like. Unless otherwise specified, each instance of analkenyl group is independently optionally substituted, i.e.,unsubstituted (an “unsubstituted alkenyl”) or substituted (a“substituted alkenyl”) with one or more substituents e.g., for instancefrom 1 to 5 substituents, 1 to 3 substituents, or 1 substituent. Incertain embodiments, the alkenyl group is unsubstituted C₂₋₁₀ alkenyl.In certain embodiments, the alkenyl group is substituted C₂₋₁₀ alkenyl.

“Alkynyl” refers to a radical of a straightchain or branched hydrocarbongroup having from 2 to 20 carbon atoms, one or more carboncarbon triplebonds (e.g., 1, 2, 3, or 4 carbon-carbon triple bonds), and optionallyone or more carboncarbon double bonds (e.g., 1, 2, 3, or 4 carboncarbondouble bonds) (“C₂₋₂₀ alkynyl”). In certain embodiments, alkynyl doesnot contain any double bonds. In some embodiments, an alkynyl group has2 to 10 carbon atoms (“C₂₋₁₀ alkynyl”). In some embodiments, an alkynylgroup has 2 to 9 carbon atoms (“C₂₋₉ alkynyl”). In some embodiments, analkynyl group has 2 to 8 carbon atoms (“C₂₋₈ alkynyl”). In someembodiments, an alkynyl group has 2 to 7 carbon atoms (“C₂₋₇ alkynyl”).In some embodiments, an alkynyl group has 2 to 6 carbon atoms (“C₂₋₆alkynyl”). In some embodiments, an alkynyl group has 2 to 5 carbon atoms(“C₂₋₅ alkynyl”). In some embodiments, an alkynyl group has 2 to 4carbon atoms (“C₂₋₄ alkynyl”). In some embodiments, an alkynyl group has2 to 3 carbon atoms (“C₂₋₃ alkynyl”). In some embodiments, an alkynylgroup has 2 carbon atoms (“C₂ alkynyl”). The one or more carboncarbontriple bonds can be internal (such as in 2butynyl) or terminal (such asin 1butynyl). Examples of C₂₋₄ alkynyl groups include, withoutlimitation, ethynyl (C₂), 1-propynyl (C₃), 2-propynyl (C₃), 1-butynyl(C₄), 2-butynyl (C₄), and the like. Examples of C₂₋₆ alkenyl groupsinclude the aforementioned C₂₋₄ alkynyl groups as well as pentynyl (C₅),hexynyl (C₆), and the like. Additional examples of alkynyl includeheptynyl (C₇), octynyl (C₈), and the like. Unless otherwise specified,each instance of an alkynyl group is independently optionallysubstituted, i.e., unsubstituted (an “unsubstituted alkynyl”) orsubstituted (a “substituted alkynyl”) with one or more substituents;e.g., for instance from 1 to 5 substituents, 1 to 3 substituents, or 1substituent. In certain embodiments, the alkynyl group is unsubstitutedC₂₋₁₀ alkynyl. In certain embodiments, the alkynyl group is substitutedC₂₋₁₀ alkynyl.

The term “heteroalkyl,” as used herein, refers to an alkyl group, asdefined herein, which further comprises 1 or more (e.g., 1, 2, 3, or 4)heteroatoms (e.g., oxygen, sulfur, nitrogen, boron, silicon, phosphorus)within the parent chain, wherein the one or more heteroatoms is insertedbetween adjacent carbon atoms within the parent carbon chain and/or oneor more heteroatoms is inserted between a carbon atom and the parentmolecule, i.e., between the point of attachment. In certain embodiments,a heteroalkyl group refers to a saturated group having from 1 to 10carbon atoms and 1, 2, 3, or 4 heteroatoms (“heteroC₁₋₁₀ alkyl”). Insome embodiments, a heteroalkyl group is a saturated group having 1 to 9carbon atoms and 1, 2, 3, or 4 heteroatoms (“heteroC₁₋₉ alkyl”). In someembodiments, a heteroalkyl group is a saturated group having 1 to 8carbon atoms and 1, 2, 3, or 4 heteroatoms (“heteroC₁₋₈ alkyl”). In someembodiments, a heteroalkyl group is a saturated group having 1 to 7carbon atoms and 1, 2, 3, or 4 heteroatoms (“heteroC₁₋₇ alkyl”). In someembodiments, a heteroalkyl group is a group having 1 to 6 carbon atomsand 1, 2, or 3 heteroatoms (“heteroC₁₋₆ alkyl”). In some embodiments, aheteroalkyl group is a saturated group having 1 to 5 carbon atoms and 1or 2 heteroatoms (“heteroC₁₋₅ alkyl”). In some embodiments, aheteroalkyl group is a saturated group having 1 to 4 carbon atoms andfor 2 heteroatoms (“heteroC₁₋₄ alkyl”). In some embodiments, aheteroalkyl group is a saturated group having 1 to 3 carbon atoms and 1heteroatom (“heteroC₁₋₃ alkyl”). In some embodiments, a heteroalkylgroup is a saturated group having 1 to 2 carbon atoms and 1 heteroatom(“heteroC₁₋₂ alkyl”). In some embodiments, a heteroalkyl group is asaturated group having 1 carbon atom and 1 heteroatom (“heteroC₁alkyl”). In some embodiments, a heteroalkyl group is a saturated grouphaving 2 to 6 carbon atoms and 1 or 2 heteroatoms (“heteroC₂₋₆ alkyl”).Unless otherwise specified, each instance of a heteroalkyl group isindependently unsubstituted (an “unsubstituted heteroalkyl”) orsubstituted (a “substituted heteroalkyl”) with one or more substituents.In certain embodiments, the heteroalkyl group is an unsubstitutedheteroC₁₋₁₀ alkyl. In certain embodiments, the heteroalkyl group is asubstituted heteroC₁₋₁₀ alkyl.

“Aryl” refers to a radical of a monocyclic or polycyclic (e.g., bicyclicor tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 7Celectrons shared in a cyclic array) having 6-14 ring carbon atoms andzero heteroatoms provided in the aromatic ring system (“C₆₋₁₄ aryl”). Insome embodiments, an aryl group has six ring carbon atoms (“C₆ aryl”;e.g., phenyl). In some embodiments, an aryl group has ten ring carbonatoms (“C₁₀ aryl”; e.g., naphthyl such as 1-naphthyl and 2-naphthyl). Insome embodiments, an aryl group has fourteen ring carbon atoms (“C₁₄aryl”; e.g., anthracyl). “Aryl” also includes ring systems wherein thearyl ring, as defined above, is fused with one or more carbocyclyl orheterocyclyl groups wherein the radical or point of attachment is on thearyl ring, and in such instances, the number of carbon atoms continue todesignate the number of carbon atoms in the aryl ring system. Typicalaryl groups include, but are not limited to, groups derived fromaceanthrylene, acenaphthylene, acephenanthrylene, anthracene, azulene,benzene, chrysene, coronene, fluoranthene, fluorene, hexacene,hexaphene, hexalene, as-indacene, s-indacene, indane, indene,naphthalene, octacene, octaphene, octalene, ovalene, penta-2,4-diene,pentacene, pentalene, pentaphene, perylene, phenalene, phenanthrene,picene, pleiadene, pyrene, pyranthrene, rubicene, triphenylene, andtrinaphthalene. Particularly aryl groups include phenyl, naphthyl,indenyl, and tetrahydronaphthyl. Unless otherwise specified, eachinstance of an aryl group is independently optionally substituted, i.e.,unsubstituted (an “unsubstituted aryl”) or substituted (a “substitutedaryl”) with one or more substituents. In certain embodiments, the arylgroup is unsubstituted C₆₋₁₄ aryl. In certain embodiments, the arylgroup is substituted C₆₋₁₄ aryl.

In certain embodiments, an aryl group substituted with one or more ofgroups selected from halo, C₁₋₈ alkyl, C₁₋₈ haloalkyl, cyano, hydroxy,C₁₋₈ alkoxy, and amino.

Examples of representative substituted aryls include the following

wherein one of R⁵⁶ and R⁵⁷ may be hydrogen and at least one of R⁵⁶ andR⁵⁷ is each independently selected from C₁₋₈ alkyl, C₁₋₈ haloalkyl, 4-10membered heterocyclyl, alkanoyl, C₁₋₈ alkoxy, heteroaryloxy, alkylamino,arylamino, heteroarylamino, NR⁵⁸COR⁵⁹, NR⁵⁸SOR⁵⁹NR⁵⁸SO₂R⁵⁹, COOalkyl,COOaryl, CONR⁵⁸R⁵⁹, CONR⁵⁸OR⁵⁹, NR⁵⁸R⁵⁹, SO₂NR⁵⁸R⁵⁹, S-alkyl, SOalkyl,SO₂alkyl, Saryl, SOaryl, SO₂aryl; or R⁵⁶ and R⁵⁷ may be joined to form acyclic ring (saturated or unsaturated) from 5 to 8 atoms, optionallycontaining one or more heteroatoms selected from the group N, O, or S.R⁶⁰ and R⁶¹ are independently hydrogen, C₁₋₈ alkyl, C₁-C₄ haloalkyl,C₃-C₁₀ cycloalkyl, 4-10 membered heterocyclyl, C₆-C₁₀ aryl, substitutedC₆-C₁₀ aryl, 5-10 membered heteroaryl, or substituted 5-10 memberedheteroaryl .

“Fused aryl” refers to an aryl having two of its ring carbon in commonwith a second aryl or heteroaryl ring or with a carbocyclyl orheterocyclyl ring.

“Heteroaryl” refers to a radical of a 5-10 membered monocyclic orbicyclic 4n+2 aromatic ring system (e.g., having 6 or 10 π electronsshared in a cyclic array) having ring carbon atoms and 1-4 ringheteroatoms provided in the aromatic ring system, wherein eachheteroatom is independently selected from nitrogen, oxygen and sulfur(“5-10 membered heteroaryl”). In heteroaryl groups that contain one ormore nitrogen atoms, the point of attachment can be a carbon or nitrogenatom, as valency permits. Heteroaryl bicyclic ring systems can includeone or more heteroatoms in one or both rings. “Heteroaryl” includes ringsystems wherein the heteroaryl ring, as defined above, is fused with oneor more carbocyclyl or heterocyclyl groups wherein the point ofattachment is on the heteroaryl ring, and in such instances, the numberof ring members continue to designate the number of ring members in theheteroaryl ring system. “Heteroaryl” also includes ring systems whereinthe heteroaryl ring, as defined above, is fused with one or more arylgroups wherein the point of attachment is either on the aryl orheteroaryl ring, and in such instances, the number of ring membersdesignates the number of ring members in the fused (aryl/heteroaryl)ring system. Bicyclic heteroaryl groups wherein one ring does notcontain a heteroatom (e.g., indolyl, quinolinyl, carbazolyl, and thelike) the point of attachment can be on either ring, i.e., either thering bearing a heteroatom (e.g., 2-indolyl) or the ring that does notcontain a heteroatom (e.g., 5-indolyl).

In some embodiments, a heteroaryl group is a 5-10 membered aromatic ringsystem having ring carbon atoms and 1-4 ring heteroatoms provided in thearomatic ring system, wherein each heteroatom is independently selectedfrom nitrogen, oxygen, and sulfur (“5-10 membered heteroaryl”). In someembodiments, a heteroaryl group is a 5-8 membered aromatic ring systemhaving ring carbon atoms and 1-4 ring heteroatoms provided in thearomatic ring system, wherein each heteroatom is independently selectedfrom nitrogen, oxygen, and sulfur (“5-8 membered heteroaryl”). In someembodiments, a heteroaryl group is a 5-6 membered aromatic ring systemhaving ring carbon atoms and 1-4 ring heteroatoms provided in thearomatic ring system, wherein each heteroatom is independently selectedfrom nitrogen, oxygen, and sulfur (“5-6 membered heteroaryl”). In someembodiments, the 5-6 membered heteroaryl has 1-3 ring heteroatomsselected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6membered heteroaryl has 1-2 ring heteroatoms selected from nitrogen,oxygen, and sulfur. In some embodiments, the 5-6 membered heteroaryl has1 ring heteroatom selected from nitrogen, oxygen, and sulfur. Unlessotherwise specified, each instance of a heteroaryl group isindependently optionally substituted, i.e., unsubstituted (an“unsubstituted heteroaryl”) or substituted (a “substituted heteroaryl”)with one or more substituents. In certain embodiments, the heteroarylgroup is unsubstituted 5-14 membered heteroaryl. In certain embodiments,the heteroaryl group is substituted 5-14 membered heteroaryl.

Exemplary 5-membered heteroaryl groups containing one heteroatominclude, without limitation, pyrrolyl, furanyl and thiophenyl. Exemplary5-membered heteroaryl groups containing two heteroatoms include, withoutlimitation, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, andisothiazolyl. Exemplary 5-membered heteroaryl groups containing threeheteroatoms include, without limitation, triazolyl, oxadiazolyl, andthiadiazolyl. Exemplary 5-membered heteroaryl groups containing fourheteroatoms include, without limitation, tetrazolyl. Exemplary6-membered heteroaryl groups containing one heteroatom include, withoutlimitation, pyridinyl. Exemplary 6-membered heteroaryl groups containingtwo heteroatoms include, without limitation, pyridazinyl, pyrimidinyl,and pyrazinyl. Exemplary 6membered heteroaryl groups containing three orfour heteroatoms include, without limitation, triazinyl and tetrazinyl,respectively. Exemplary 7-membered heteroaryl groups containing oneheteroatom include, without limitation, azepinyl, oxepinyl, andthiepinyl. Exemplary 5,6-bicyclic heteroaryl groups include, withoutlimitation, indolyl, isoindolyl, indazolyl, benzotriazolyl,benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzoisofuranyl,benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl,benzthiazolyl, benzisothiazolyl, benzthiadiazolyl, indolizinyl, andpurinyl. Exemplary 6,6-bicyclic heteroaryl groups include, withoutlimitation, naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl,cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl.

Examples of representative heteroaryls include the following:

wherein each Z is selected from carbonyl, N, NR⁶⁵, O, and S; and R⁶⁵ isindependently hydrogen, C₁-C₈ alkyl, C₃-C₁₀ cycloalkyl, 4-10 memberedheterocyclyl, C₆-C₁₀ aryl, and 5-10 membered heteroaryl.

“carbocyclyl” or “carbocyclic” refers to a radical of a nonaromaticcyclic hydrocarbon group having from 3 to 10 ring carbon atoms (“C₃₋₁₀)carbocyclyl”) and zero heteroatoms in the nonaromatic ring system. Insome embodiments, a carbocyclyl group has 3 to 8 ring carbon atoms(“C₃₋₈ carbocyclyl”). In some embodiments, a carbocyclyl group has 3 to6 ring carbon atoms (“C₃₋₆ carbocyclyl”). In some embodiments, acarbocyclyl group has 3 to 6 ring carbon atoms (“C₃₋₆ carbocyclyl”). Insome embodiments, a carbocyclyl group has 5 to 10 ring carbon atoms(“C₅₋₁₀ carbocyclyl”). Exemplary C₃₋₆ carbocyclyl groups include,without limitation, cyclopropyl (C₃), cyclopropenyl (C₃), cyclobutyl(C₄), cyclobutenyl (C₄), cyclopentyl (C₅), cyclopentenyl (C₅),cyclohexyl (C₆), cyclohexenyl (C₆), cyclohexadienyl (C₆), and the like.Exemplary C₃₋₈ carbocyclyl groups include, without limitation, theaforementioned C₃₋₆ carbocyclyl groups as well as cycloheptyl (C₇),cycloheptenyl (C₇), cycloheptadienyl (C₇), cycloheptatrienyl (C₇),cyclooctyl (C₈), cyclooctenyl (C₈), bicyclo[2.2.1]heptanyl (C₇),bicyclo[2.2.2]octanyl (C₈), and the like. Exemplary C₃₋₁₀ carbocyclylgroups include, without limitation, the aforementioned C₃₋₈ carbocyclylgroups as well as cyclononyl (C₉), cyclononenyl (C₉), cyclodecyl (C₁₀),cyclodecenyl (C₁₀), octahydro-1H-indenyl (C₉), decahydronaphthalenyl(C₁₀), spiro[4.5]decanyl (C₁₀), and the like. As the foregoing examplesillustrate, in certain embodiments, the carbocyclyl group is eithermonocyclic (“monocyclic carbocyclyl”) or contain a fused, bridged orspiro ring system such as a bicyclic system (“bicyclic carbocyclyl”) andcan be saturated or can be partially unsaturated. “Carbocyclyl” alsoincludes ring systems wherein the carbocyclyl ring, as defined above, isfused with one or more aryl or heteroaryl groups wherein the point ofattachment is on the carbocyclyl ring, and in such instances, the numberof carbons continue to designate the number of carbons in thecarbocyclic ring system. Unless otherwise specified, each instance of acarbocyclyl group is independently optionally substituted, i.e.,unsubstituted (an “unsubstituted carbocyclyl”) or substituted (a“substituted carbocyclyl”) with one or more substituents. In certainembodiments, the carbocyclyl group is unsubstituted C₃₋₁₀ carbocyclyl.In certain embodiments, the carbocyclyl group is a substituted C₃₋₁₀carbocyclyl.

In some embodiments, “carbocyclyl” is a monocyclic, saturatedcarbocyclyl group having from 3 to 10 ring carbon atoms (“C₃₋₁₀cycloalkyl”). In some embodiments, a cycloalkyl group has 3 to 8 ringcarbon atoms (“C₃₋₈ cycloalkyl”). In some embodiments, a cycloalkylgroup has 3 to 6 ring carbon atoms (“C₃₋₆ cycloalkyl”). In someembodiments, a cycloalkyl group has 5 to 6 ring carbon atoms (“C₅₋₆cycloalkyl”). In some embodiments, a cycloalkyl group has 5 to 10 ringcarbon atoms (“C₅₋₁₀ cycloalkyl”). Examples of C₅₋₆ cycloalkyl groupsinclude cyclopentyl (C₅) and cyclohexyl (C₅). Examples of C₃₋₆cycloalkyl groups include the aforementioned C₅₋₆ cycloalkyl groups aswell as cyclopropyl (C₃) and cyclobutyl (C₄). Examples of C₃₋₈cycloalkyl groups include the aforementioned C₃₋₆ cycloalkyl groups aswell as cycloheptyl (C₇) and cyclooctyl (C₈). Unless otherwisespecified, each instance of a cycloalkyl group is independentlyunsubstituted (an “unsubstituted cycloalkyl”) or substituted (a“substituted cycloalkyl”) with one or more substituents. In certainembodiments, the cycloalkyl group is unsubstituted C₃₋₁₀ cycloalkyl. Incertain embodiments, the cycloalkyl group is substituted C₃₋₁₀cycloalkyl.

“Heterocyclyl” or “heterocyclic” refers to a radical of a 3- to10-membered non-aromatic ring system having ring carbon atoms and 1 to 4ring heteroatoms, wherein each heteroatom is independently selected fromnitrogen, oxygen, sulfur, boron, phosphorus, and silicon (“3-10 memberedheterocyclyl”). In heterocyclyl groups that contain one or more nitrogenatoms, the point of attachment can be a carbon or nitrogen atom, asvalency permits. A heterocyclyl group can either be monocyclic(“monocyclic heterocyclyl”) or a fused, bridged or spiro ring systemsuch as a bicyclic system (“bicyclic heterocyclyl”), and can besaturated or can be partially unsaturated. Heterocyclyl bicyclic ringsystems can include one or more heteroatoms in one or both rings.“Heterocyclyl” also includes ring systems wherein the heterocyclyl ring,as defined above, is fused with one or more carbocyclyl groups whereinthe point of attachment is either on the carbocyclyl or heterocyclylring, or ring systems wherein the heterocyclyl ring, as defined above,is fused with one or more aryl or heteroaryl groups, wherein the pointof attachment is on the heterocyclyl ring, and in such instances, thenumber of ring members continue to designate the number of ring membersin the heterocyclyl ring system. Unless otherwise specified, eachinstance of heterocyclyl is independently optionally substituted, i.e.,unsubstituted (an “unsubstituted heterocyclyl”) or substituted (a“substituted heterocyclyl”) with one or more substituents. In certainembodiments, the heterocyclyl group is unsubstituted 3-10 memberedheterocyclyl. In certain embodiments, the heterocyclyl group issubstituted 3-10 membered heterocyclyl.

In some embodiments, a heterocyclyl group is a 5-10 membered nonaromaticring system having ring carbon atoms and 1-4 ring heteroatoms, whereineach heteroatom is independently selected from nitrogen, oxygen, sulfur,boron, phosphorus, and silicon (“5-10 membered heterocyclyl”). In someembodiments, a heterocyclyl group is a 5-8 membered non-aromatic ringsystem having ring carbon atoms and 1-4 ring heteroatoms, wherein eachheteroatom is independently selected from nitrogen, oxygen, and sulfur(“5-8 membered heterocyclyl”). In some embodiments, a heterocyclyl groupis a 5-6 membered non-aromatic ring system having ring carbon atoms and1-4 ring heteroatoms, wherein each heteroatom is independently selectedfrom nitrogen, oxygen, and sulfur (“5-6 membered heterocyclyl”). In someembodiments, the 5-6 membered heterocyclyl has 1-3 ring heteroatomsselected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6membered heterocyclyl has 1-2 ring heteroatoms selected from nitrogen,oxygen, and sulfur. In some embodiments, the 5-6 membered heterocyclylhas one ring heteroatom selected from nitrogen, oxygen, and sulfur.

Exemplary 3-membered heterocyclyl groups containing one heteroatominclude, without limitation, azirdinyl, oxiranyl, thiorenyl. Exemplary4-membered heterocyclyl groups containing one heteroatom include,without limitation, azetidinyl, oxetanyl and thietanyl. Exemplary5-membered heterocyclyl groups containing one heteroatom include,without limitation, tetrahydrofuranyl, dihydrofuranyl,tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyland pyrrolyl-2,5-dione. Exemplary 5-membered heterocyclyl groupscontaining two heteroatoms include, without limitation, dioxolanyl,oxasulfuranyl, disulfuranyl, and oxazolidin-2-one. Exemplary 5-memberedheterocyclyl groups containing three heteroatoms include, withoutlimitation, triazolinyl, oxadiazolinyl, and thiadiazolinyl. Exemplary6-membered heterocyclyl groups containing one heteroatom include,without limitation, piperidinyl, tetrahydropyranyl, dihydropyridinyl,and thianyl. Exemplary 6-membered heterocyclyl groups containing twoheteroatoms include, without limitation, piperazinyl, morpholinyl,dithianyl, dioxanyl. Exemplary 6-membered heterocyclyl groups containingtwo heteroatoms include, without limitation, triazinanyl. Exemplary7-membered heterocyclyl groups containing one heteroatom include,without limitation, azepanyl, oxepanyl and thiepanyl. Exemplary8-membered heterocyclyl groups containing one heteroatom include,without limitation, azocanyl, oxecanyl and thiocanyl. Exemplary5-membered heterocyclyl groups fused to a C₆ aryl ring (also referred toherein as a 5,6-bicyclic heterocyclic ring) include, without limitation,indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl,benzoxazolinonyl, and the like. Exemplary 6-membered heterocyclyl groupsfused to an aryl ring (also referred to herein as a 6,6-bicyclicheterocyclic ring) include, without limitation, tetrahydroquinolinyl,tetrahydroisoquinolinyl, and the like.

“Nitrogen-containing heterocyclyl” group means a 4- to 7-memberednon-aromatic cyclic group containing at least one nitrogen atom, forexample, but without limitation, morpholine, piperidine (e.g.2-piperidinyl, 3-piperidinyl and 4-piperidinyl), pyrrolidine (e.g.2-pyrrolidinyl and 3-pyrrolidinyl), azetidine, pyrrolidone, imidazoline,imidazolidinone, 2-pyrazoline, pyrazolidine, piperazine, and N-alkylpiperazines such as N-methyl piperazine. Particular examples includeazetidine, piperidone and piperazone.

“Hetero” when used to describe a compound or a group present on acompound means that one or more carbon atoms in the compound or grouphave been replaced by a nitrogen, oxygen, or sulfur heteroatom. Heteromay be applied to any of the hydrocarbyl groups described above such asalkyl, e.g., heteroalkyl, cycloalkyl, e.g., heterocyclyl, aryl, e.g,.heteroaryl, cycloalkenyl, e.g,. cycloheteroalkenyl, and the like havingfrom 1 to 5, and particularly from 1 to 3 heteroatoms.

“Acyl” refers to a radical —C(O)R²⁰, where R²⁰ is hydrogen, substitutedor unsubstituted alkyl, substituted or unsubstituted alkenyl,substituted or unsubstituted alkynyl, substituted or unsubstitutedcarbocyclyl, substituted or unsubstituted heterocyclyl, substituted orunsubstituted aryl, or substituted or unsubstituted heteroaryl, asdefined herein. “Alkanoyl” is an acyl group wherein R²⁰ is a group otherthan hydrogen. Representative acyl groups include, but are not limitedto, formyl (—CHO), acetyl (—C(═O)CH₃), cyclohexylcarbonyl,cyclohexylmethylcarbonyl, benzoyl (—C(═O)Ph), benzylcarbonyl(—C(═O)CH₂Ph), —C(O)—C₁₋₈ alkyl, —C(O)—(CH₂)_(t)(C₆-C₁₀ aryl),—C(O)—(CH₂)_(t)(5-10 membered heteroaryl), C(O)—(CH₂)_(t)(C₃-C₁₀ tocycloalkyl), and —C(O)—(CH₂)_(t)(4-10 membered heterocyclyl), wherein tis an integer from 0 to 4. In certain embodiments, R²¹ is C₁₋₈ alkyl,substituted with halo or hydroxy; or C₃-C₁₀ cycloalkyl, 4-10 memberedheterocyclyl, C₆-C₁₀ aryl, arylalkyl, 5-10 membered heteroaryl orheteroarylalkyl, each of which is substituted with unsubstituted C₁-C₄alkyl, halo, unsubstituted C₁-C₄ alkoxy, unsubstituted C₁-C₄ haloalkyl,unsubstituted C₁-C₄ hydroxyalkyl, or unsubstituted C₁-C₄ haloalkoxy orhydroxy.

“Alkoxy” refers to the group —OR²⁹ where R²⁹ is substituted orunsubstituted alkyl, substituted or unsubstituted alkenyl, substitutedor unsubstituted alkynyl, substituted or unsubstituted carbocyclyl,substituted or unsubstituted heterocyclyl, substituted or unsubstitutedaryl, or substituted or unsubstituted heteroaryl. Particular alkoxygroups are methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy,tert-butoxy, sec-butoxy, n-pentoxy, n-hexoxy, and 1,2-dimethylbutoxy.Particular alkoxy groups are lower alkoxy, i.e. with between 1 and 6carbon atoms. Further particular alkoxy groups have between 1 and 4carbon atoms.

In certain embodiments, R²⁹ is a group that has 1 or more substituents,for instance from 1 to 5 substituents, and particularly from 1 to 3substituents, in particular 1 substituent, selected from the groupconsisting of amino, substituted amino, C₆-C₁₀ aryl, aryloxy, carboxyl,cyano, C₃-C₁₀ cycloalkyl, 4-10 membered heterocyclyl, halogen, 5-10membered heteroaryl, hydroxyl, nitro, thioalkoxy, thioaryloxy, thiol,alkyl-S(O)—, aryl-S(O)—, alkyl-S(O)₂— and aryl-S(O)₂—. Exemplary‘substituted alkoxy’ groups include, but are not limited to,—O—(CH₂)_(t)(C₆-C₁₀ aryl), —O—(CH₂)_(t)(5-10 membered heteroaryl),—O—(CH₂)_(t)(C₃-C₁₀ cycloalkyl), and —O—(CH₂)_(t)(4-10 memberedheterocyclyl), wherein t is an integer from 0 to 4 and any aryl,heteroaryl, cycloalkyl or heterocyclyl groups present, may themselves besubstituted by unsubstituted C₁-C₄ alkyl, halo, unsubstituted C₁-C₄alkoxy, unsubstituted C₁-C₄ haloalkyl, unsubstituted C₁-C₄ hydroxyalkyl,or unsubstituted C₁-C₄ haloalkoxy or hydroxy. Particular exemplary‘substituted alkoxy’ groups are —OCF₃, —OCH₂CF₃, —OCH₂Ph,—OCH₂-cyclopropyl, —OCH₂CH₂OH, and —OCH₂CH₂NMe₂.

“Amino” refers to the radical —NH₂.

“Oxo group” refers to —C(═O)—.

“Substituted amino” refers to an amino group of the formula —N(R³⁸)₂wherein R³⁸ is hydrogen, substituted or unsubstituted alkyl, substitutedor unsubstitued alkenyl, substituted or unsubstitued alkynyl,substituted or unsubstitued carbocyclyl, substituted or unsubstitutedheterocyclyl, substituted or unsubstituted aryl, substituted orunsubstitued heteroaryl, or an amino protecting group, wherein at leastone of R³⁸ is not a hydrogen. In certain embodiments, each R³⁸ isindependently selected from hydrogen, C₁₋₈ alkyl, C₃-C₈ alkenyl, C₃-C₈alkynyl, C₆-C₁₀ aryl, 5-10 membered heteroaryl, 4-10 memberedheterocyclyl, or C₃-C₁₀ cycloalkyl; or C₁-C₈ alkyl, substituted withhalo or hydroxy; C₃-C₈ alkenyl, substituted with halo or hydroxy; C₃-C₈alkynyl, substituted with halo or hydroxy, or —(CH₂)_(t)(C₆-C₁₀ aryl),—(CH₂)_(t)(5-10 membered heteroaryl), —(CH₂)_(t)(C₃-C₁₀ cycloalkyl), or—(CH₂)_(t)(4-10 membered heterocyclyl), wherein t is an integer between0 and 8, each of which is substituted by unsubstituted C₁-C₄ alkyl,halo, unsubstituted C₁-C₄ alkoxy, unsubstituted C₁-C₄ haloalkyl,unsubstituted C₁-C₄ hydroxyalkyl, or unsubstituted C₁-C₄ haloalkoxy orhydroxy; or both R³⁸ groups are joined to form an alkylene group.

Exemplary “substituted amino” groups include, but are not limited to,—NR³⁹—C₁-C₈ alkyl, —NR³⁹—(CH₂)_(t)(C₆-C₁₀ aryl), —NR³⁹—(CH₂)_(t)(5-10membered heteroaryl), —NR³⁹—(CH₂)_(t)(C₃-C₁₀ cycloalkyl), and—NR³⁹—(CH₂)_(t)(4-10 membered heterocyclyl), wherein t is an integerfrom 0 to 4, for instance 1 or 2, each R³⁹ independently represents H orC₁-C₈ alkyl; and any alkyl groups present, may themselves be substitutedby halo, substituted or unsubstituted amino, or hydroxy; and any aryl,heteroaryl, cycloalkyl, or heterocyclyl groups present, may themselvesbe substituted by unsubstituted C₁-C₄ alkyl, halo, unsubstituted C₁-C₄alkoxy, unsubstituted C₁-C₄ haloalkyl, unsubstituted C₁-C₄ hydroxyalkyl,or unsubstituted C₁-C₄ haloalkoxy or hydroxy. For the avoidance of doubtthe term ‘substituted amino’ includes the groups alkylamino, substitutedalkylamino, alkylarylamino, substituted alkylarylamino, arylamino,substituted arylamino, dialkylamino, and substituted dialkylamino asdefined below. Substituted amino encompasses both monosubstituted aminoand disubstituted amino groups.

“Carboxy” refers to the radical —C(O)OH.

“Cyano” refers to the radical —CN.

“Halo” or “halogen” refers to fluoro (F), chloro (Cl), bromo (Br), andiodo (I). In certain embodiments, the halo group is either fluoro orchloro.

“Haloalkyl” refers to an alkyl radical in which the alkyl group issubstituted with one or more halogens. Typical haloalkyl groups include,but are not limited to, trifluoromethyl, difluoromethyl, fluoromethyl,chloromethyl, dichloromethyl, dibromoethyl, tribromomethyl,tetrafluoroethyl, and the like.

“Hydroxy” refers to the radical —OH.

“Nitro” refers to the radical —NO₂.

“Thioketo” refers to the group ═S.

Alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroarylgroups, as defined herein, are optionally substituted (e.g.,“substituted” or “unsubstituted” alkyl, “substituted” or “unsubstituted”alkenyl, “substituted” or “unsubstituted” alkynyl, “substituted” or“unsubstituted” carbocyclyl, “substituted” or “unsubstituted”heterocyclyl, “substituted” or “unsubstituted” aryl or “substituted” or“unsubstituted” heteroaryl group). In general, the term “substituted”,whether preceded by the term “optionally” or not, means that at leastone hydrogen present on a group (e.g., a carbon or nitrogen atom) isreplaced with a permissible substituent, e.g., a substituent which uponsubstitution results in a stable compound, e.g., a compound which doesnot spontaneously undergo transformation such as by rearrangement,cyclization, elimination, or other reaction. Unless otherwise indicated,a “substituted” group has a substituent at one or more substitutablepositions of the group, and when more than one position in any givenstructure is substituted, the substituent is either the same ordifferent at each position. The term “substituted” is contemplated toinclude substitution with all permissible substituents of organiccompounds, any of the substituents described herein that results in theformation of a stable compound. The present invention contemplates anyand all such combinations in order to arrive at a stable compound. Forpurposes of this invention, heteroatoms such as nitrogen may havehydrogen substituents and/or any suitable substituent as describedherein which satisfy the valencies of the heteroatoms and results in theformation of a stable moiety.

Exemplary carbon atom substituents include, but are not limited to,halogen, —CN, —NO₂, —N₃, —SO₂H, —SO₃H, —OH, —OR^(aa), —ON(R^(bb))₂,—N(R^(bb))₂, —N(R^(bb))₃ ⁺X⁻, —N(OR^(cc))R^(bb), —SH, —SR^(aa),—SSR^(cc), —C(═O)R^(aa), —CO₂H, —CHO, —C(OR^(cc))₂, —CO₂R^(aa),—OC(═O)R^(aa), —OCO₂R^(aa), —C(═O)N(R^(bb))₂, —OC(═O)N(R^(bb))₂,—NR^(bb)C(═O)R^(aa), —NR^(bb)CO₂R^(aa), —NR^(bb)C(═O)N(R^(bb))₂,—C(═NR_(bb))R^(aa), —C(═NR^(bb))OR^(aa), —OC(═NR^(bb))R^(aa),—OC(═NR^(bb))OR^(aa), —C(═NR^(bb))N(R^(bb))₂, —OC(═NR^(bb))N(R^(bb))₂,—NR^(bb)C(═NR^(bb))N(R^(bb))₂, —C(═O)NR^(bb)SO₂R^(aa),—NR^(bb)SO₂R^(aa), —SO₂N(R^(bb))₂, —SO₂R^(aa), —SO₂OR^(aa), —OSO₂R^(aa),—S(═O)R^(aa), —OS(═O)R^(aa), —Si(R^(aa))₃, —OSi (R^(aa))₃—C(═S)N(R^(bb))₂, —C(═O)SR^(aa), —C(═S)SR^(aa), —SC(═S)SR^(aa),—SC(═O)SR^(aa), —OC(═O)SR^(aa), —SC(═O)OR^(aa), —SC(═O)R^(aa),—P(═O)₂R^(aa), —OP(═O)₂R^(aa), —P(═O)(R^(aa))₂, —OP(═O)(R^(aa))₂,—OP(═O)(OR^(cc))₂, —P(═O)₂N(R^(bb))₂, —OP(═O)₂N(R^(bb))₂,—P(═O)(NR^(bb))₂, —OP(═O)(NR^(bb))₂, —NR^(bb)P(═O)(OR^(cc))₂,—NR^(bb)P(═O) (NR^(bb))₂, —P(R^(cc))₂, —P(R^(cc))₃, —OP(R^(cc))₂,—OP(R^(cc))₃, —B(R^(aa))₂, —B(OR^(cc))₂, —BR^(aa)(OR^(cc)), C₁₋₁₀ alkyl,C₁₋₁₀ haloalkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, C₃₋₁₀ carbocyclyl, 3-14membered heterocyclyl, C₆₋₁₄ aryl, and 5-14 membered heteroaryl, whereineach alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, andheteroaryl is independently substituted with 0,1, 2, 3, 4, or 5 R^(dd)groups; or two geminal hydrogens on a carbon atom are replaced with thegroup ═O, ═S, ═NN(R^(bb))₂, ═NNR^(bb)C(═O)R^(aa), ═NNR^(bb)C(═O)OR^(aa),═NNR^(bb)S(═O)₂R^(aa), ═NR^(bb), or ═NOR^(cc);

each instance of R^(aa) is, independently, selected from C₁₋₁₀ alkyl,C₁₋₁₀ haloalkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, C₃₋₁₀ carbocyclyl, 3-14membered heterocyclyl, C₆₋₁₄ aryl, and 5-14 membered heteroaryl, or twoR^(aa) groups are joined to form a 3-14 membered heterocyclyl or 5-14membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl,carbocyclyl, heterocyclyl, aryl, and heteroaryl is independentlysubstituted with 0,1, 2, 3, 4, or 5 R^(dd) groups;

each instance of R^(bb) is, independently, selected from hydrogen, —OH,—OR^(aa), —N(R^(cc))₂, —CN, —C(═O)R^(aa), —C(═O)N(R^(cc))₂, —CO₂R^(aa),—SO₂R^(aa), —C(═NR^(cc))OR^(aa), —C(═NR^(cc))N(R^(cc))₂, —SO₂N(R^(cc))₂,—SO₂R^(cc), —SO₂OR^(cc), —SOR^(aa), —C(═S)N(R^(cc))₂, —C(═O)SR^(cc),—C(═S)SR^(cc), —P(═O)₂R^(aa), —P(═O)(R^(aa))₂, —P(═O)₂N(R^(cc))₂,—P(═O)(NR^(cc))₂, C₁₋₁₀ alkyl, C₁₋₁₀ haloalkyl, C₂₋₁₀ alkenyl, C₂₋₁₀alkynyl, C₃₋₁₀ carbocyclyl, 3-14 membered heterocyclyl, C₆₋₁₄ aryl, and5-14 membered heteroaryl, or two R^(bb) groups are joined to form a 3-14membered heterocyclyl or 5-14 membered heteroaryl ring, wherein eachalkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroarylis independently substituted with 0, 1, 2, 3, 4, or 5 R^(dd) groups;

each instance of RCC is, independently, selected from hydrogen, C₁₋₁₀alkyl, C₁₋₁₀ haloalkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, C₃₋₁₀ carbocyclyl,3-14 membered heterocyclyl, C₆₋₁₄ aryl, and 5-14 membered heteroaryl, ortwo R^(cc) groups are joined to form a 3-14 membered heterocyclyl or5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl,carbocyclyl, heterocyclyl, aryl, and heteroaryl is independentlysubstituted with 0, 1, 2, 3, 4, or 5 R^(dd) groups;

each instance of R^(dd) is, independently, selected from halogen, —CN,—NO₂, —N₃, —SO₂H, —SO₃H, —OH, —OR^(ee), —ON(R^(ff))₂, —N(R^(ff))₂,—N(R^(ff))₃ ⁺X⁻, —N(OR^(ee))R^(ff), —SH, —SR^(ee), —SSR^(ee),—C(═O)R^(ee), —CO₂H, —CO₂R^(ee), —OC(═O)R^(ee), —OCO₂R^(ee),—C(═O)N(R^(ff))₂, —OC(═O)N(R^(ff))₂, —NR^(ff)C(═O)R^(ee),—NR^(ff)CO₂R^(ee), —NR^(ff)C(═O)N(R^(ff))₂, —C(═NR^(ff))OR^(ee),—OC(═NR^(ff))R^(ee), —OC(═NR^(ff))OR^(ee), —C(═NR^(ff))N(R^(ff))₂,—OC(═NR^(ff))N(R^(ff))₂, —NR^(ff)C(═NR^(ff))N(R^(ff))₂,—NR^(ff)SO₂R^(ee), —SO₂N(R^(ff))₂, —SO₂R^(ee), —SO₂OR^(ee), —OSO₂R^(ee),—S(═O)R^(ee), —Si(R^(ee))₃, —OSi(R^(ee))₃, —C(═S)N(R^(ff))₂,—C(═O)SR^(ee), —C(═S)SR^(ee), —SC(═S)SR^(ee), —P(═O)₂R^(ee),—P(═O)(R^(ee))₂, —OP(═O)(R^(ee))₂, —OP(═O)(OR^(ee))₂, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ carbocyclyl, 3-10 memberedheterocyclyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl, wherein each alkyl,alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl isindependently substituted with 0, 1, 2, 3, 4, or 5 R^(gg) groups, or twogeminal R^(dd) substituents can be joined to form ═O or ═S;

each instance of R^(ee) is, independently, selected from C₁₋₆ alkyl,C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ carbocyclyl, C₆₋₁₀aryl, 3-10 membered heterocyclyl, and 3-10 membered heteroaryl, whereineach alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, andheteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R^(gg)groups;

each instance of R^(ff) is, independently, selected from hydrogen, C₁₋₆alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ carbocyclyl,3-10 membered heterocyclyl, C₆₋₁₀ aryl and 5-10 membered heteroaryl, ortwo R^(ff) groups are joined to form a 3-14 membered heterocyclyl or5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl,carbocyclyl, heterocyclyl, aryl, and heteroaryl is independentlysubstituted with 0, 1, 2, 3, 4, or 5 R^(gg) groups; and

each instance of R^(gg) is, independently, halogen, —CN, —NO₂, —N₃,—SO₂H, —SO₃H, —OH, —OC₁₋₆ alkyl, —ON(C₁₋₆ alkyl)₂, —N(C₁₋₆ alkyl)₂,—N(C₁₋₆ alkyl)₃ ⁺X⁻, —NH(C₁₋₆ alkyl)₂ ⁺X⁻, —NH₂(C₁₋₆ alkyl) ⁺X⁻, —NH₃⁺X⁻, —N(OC₁₋₆ alkyl)(C₁₋₆ alkyl), —N(OH)(C₁₋₆ alkyl), —NH(OH), —SH,—SC₁₋₆ alkyl, —SS(C₁₋₆ alkyl), —C(═O)(C₁₋₆ alkyl), —CO₂H, —CO₂(C₁₋₆alkyl), —OC(═O)(C₁₋₆ alkyl), —OCO₂(C₁₋₆ alkyl), —C(═O)NH₂, —C(═O)N(C₁₋₆alkyl)₂, —OC(═O)NH(C₁₋₆ alkyl), —NHC(═O)(C₁₋₆ alkyl), —N(C₁₋₆alkyl)C(═O)(C₁₋₆ alkyl), —NHCO₂(C₁₋₆ alkyl), —NHC(═O)N(C₁₋₆ alkyl)₂,—NHC(═O)NH(C₁₋₆ alkyl), —NHC(═O)NH₂, —C(═NH)O(C₁₋₆ alkyl), —OC(═NH)(C₁₋₆alkyl), —OC(═NH)OC₁₋₆ alkyl, —C(═NH)N(C₁₋₆ alkyl)₂, —C(═NH)NH(C₁₋₆alkyl), —C(═NH)NH₂, —OC(═NH)N(C₁₋₆ alkyl)₂, —OC(NH)NH(C₁₋₆ alkyl),—OC(NH)NH₂, —NHC(NH)N(C₁₋₆ alkyl)₂, —NHC(═NH)NH₂, —NHSO₂(C₁₋₆ alkyl),—SO₂N(C₁₋₆ alkyl)₂, —SO₂NH(C₁₋₆ alkyl), —SO₂NH₂, —SO₂C₁₋₆ alkyl,—SO₂OC₁₋₆ alkyl, —OSO₂C₁₋₆ alkyl, —SOC₁₋₆ alkyl, —Si(C₁₋₆ alkyl)₃,—OSi(C₁₋₆ alkyl)₃ —C(═S)N(C₁₋₆ alkyl)₂, C(═S)NH(C₁₋₆ alkyl), C(═S)NH₂,—C(═O)S(C₁₋₆ alkyl), —C(═S)SC₁₋₆ alkyl, —SC(═S)SC₁₋₆ alkyl, —P(═O)₂(C₁₋₆alkyl), —P(═O)(C₁₋₆ alkyl)₂, —OP(═O)(C₁₋₆ alkyl)₂, —OP(═O)(OC₁₋₆alkyl)₂, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀carbocyclyl, C₆₋₁₀ aryl, 3-10 membered heterocyclyl, 5-10 memberedheteroaryl; or two geminal R^(gg) substituents can be joined to form ═Oor ═S; wherein X⁻ is a counterion.

A “counterion” or “anionic counterion” is a negatively charged groupassociated with a cationic quaternary amino group in order to maintainelectronic neutrality. Exemplary counterions include halide ions (e.g.,F⁻, Cl⁻, Br⁻, I⁻), NO₃ ⁻, ClO₄ ⁻, OH⁻, H₂PO₄ ⁻, HSO₄ ⁻, SO₄ ⁻ ²sulfonateions (e.g., methansulfonate, trifluoromethanesulfonate,p-toluenesulfonate, benzenesulfonate, 10-camphor sulfonate,naphthalene-2-sulfonate, naphthalene-1-sulfonic acid-5-sulfonate,ethan-1-sulfonic acid-2-sulfonate, and the like), and carboxylate ions(e.g., acetate, ethanoate, propanoate, benzoate, glycerate, lactate,tartrate, glycolate, and the like).

Nitrogen atoms can be substituted or unsubstituted as valency permits,and include primary, secondary, tertiary, and quarternary nitrogenatoms. Exemplary nitrogen atom substituents include, but are not limitedto, hydrogen, —OH, —OR^(aa), —N(R^(cc))₂, —CN, —C(═O)R^(aa),—C(═O)N(R^(cc))₂, —CO₂R^(aa), —SO₂R^(aa), —C(═NR^(bb))R^(aa),—C(═NR^(cc))OR^(aa), —C(═NR^(cc))N(R^(cc))₂, —SO₂N(R^(cc))₂, —SO₂R^(cc),—SO₂OR^(cc), —SOR^(aa), —C(═S)N(R^(cc))₂, —C(═O)SR^(cc), —C(═S)SR^(cc),—P(═O)₂R^(aa), —P(═O)(R^(aa))₂, —P(═O)₂N(R^(cc))₂, —P(═O)(NR^(cc))₂,C₁₋₁₀ alkyl, C₁₋₁₀ haloalkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, C₃₋₁₀carbocyclyl, 3-14 membered heterocyclyl, C₆₋₁₄ aryl, and 5-14 memberedheteroaryl, or two R^(cc) groups attached to a nitrogen atom are joinedto form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring,wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl,and heteroaryl is independently substituted with 0,1,2,3,4, or 5 R^(dd)groups, and wherein R^(aa), R^(bb), R^(cc) and R^(dd) are as definedabove.

These and other exemplary substituents are described in more detail inthe Detailed Description, Examples, and claims. The invention is notintended to be limited in any manner by the above exemplary listing ofsubstituents.

Other definitions

The term “pharmaceutically acceptable salt” refers to those salts whichare, within the scope of sound medical judgment, suitable for use incontact with the tissues of humans and lower animals without unduetoxicity, irritation, allergic response and the like, and arecommensurate with a reasonable benefit/risk ratio. Pharmaceuticallyacceptable salts are well known in the art. For example, Berge et al.,describes pharmaceutically acceptable salts in detail in J.Pharmaceutical Sciences (1977) 66:1-19. Pharmaceutically acceptablesalts of the compounds of this invention include those derived fromsuitable inorganic and organic acids and bases. Examples ofpharmaceutically acceptable, nontoxic acid addition salts are salts ofan amino group formed with inorganic acids such as hydrochloric acid,hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid orwith organic acids such as acetic acid, oxalic acid, maleic acid,tartaric acid, citric acid, succinic acid or malonic acid or by usingother methods used in the art such as ion exchange. Otherpharmaceutically acceptable salts include adipate, alginate, ascorbate,aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate,camphorate, camphorsulfonate, citrate, cyclopentanepropionate,digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate,glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate,hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate,lactate, laurate, lauryl sulfate, malate, maleate, malonate,methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate,oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate,phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate,tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate salts,and the like. Pharmaceutically acceptable salts derived from appropriatebases include alkali metal, alkaline earth metal, ammonium andN⁺(C₁₋₄alkyl)₄ salts. Representative alkali or alkaline earth metalsalts include sodium, lithium, potassium, calcium, magnesium, and thelike. Further pharmaceutically acceptable salts include, whenappropriate, nontoxic ammonium, quaternary ammonium, and amine cationsformed using counterions such as halide, hydroxide, carboxylate,sulfate, phosphate, nitrate, lower alkyl sulfonate, and aryl sulfonate.

A “subject” to which administration is contemplated includes, but is notlimited to, humans (i.e., a male or female of any age group, e.g., apediatric subject (e.g, infant, child, adolescent) or adult subject(e.g., young adult, middleaged adult or senior adult)) and/or anon-human animal, e.g., a mammal such as primates (e.g., cynomolgusmonkeys, rhesus monkeys), cattle, pigs, horses, sheep, goats, rodents,cats, and/or dogs. In certain embodiments, the subject is a human. Incertain embodiments, the subject is a non-human animal. The terms“human,” “patient,” and “subject” are used interchangeably herein.

Disease, disorder, and condition are used interchangeably herein.

As used herein, and unless otherwise specified, the terms “treat,”“treating” and “treatment” contemplate an action that occurs while asubject is suffering from the specified disease, disorder or condition,which reduces the severity of the disease, disorder or condition, orretards or slows the progression of the disease, disorder or condition(“therapeutic treatment”), and also contemplates an action that occursbefore a subject begins to suffer from the specified disease, disorderor condition (“prophylactic treatment”).

In general, the “effective amount” of a compound refers to an amountsufficient to elicit the desired biological response. As will beappreciated by those of ordinary skill in this art, the effective amountof a compound of the invention may vary depending on such factors as thedesired biological endpoint, the pharmacokinetics of the compound, thedisease being treated, the mode of administration, and the age, health,and condition of the subject An effective amount encompasses therapeuticand prophylactic treatment.

As used herein, and unless otherwise specified, a “therapeuticallyeffective amount” of a compound is an amount sufficient to provide atherapeutic benefit in the treatment of a disease, disorder orcondition, or to delay or minimize one or more symptoms associated withthe disease, disorder or condition. A therapeutically effective amountof a compound means an amount of therapeutic agent, alone or incombination with other therapies, which provides a therapeutic benefitin the treatment of the disease, disorder or condition. The term“therapeutically effective amount” can encompass an amount that improvesoverall therapy, reduces or avoids symptoms or causes of disease orcondition, or enhances the therapeutic efficacy of another therapeuticagent.

As used herein, and unless otherwise specified, a “prophylacticallyeffective amount” of a compound is an amount sufficient to prevent adisease, disorder or condition, or one or more symptoms associated withthe disease, disorder or condition, or prevent its recurrence. Aprophylactically effective amount of a compound means an amount of atherapeutic agent, alone or in combination with other agents, whichprovides a prophylactic benefit in the prevention of the disease,disorder or condition. The term “prophylactically effective amount” canencompass an amount that improves overall prophylaxis or enhances theprophylactic efficacy of another prophylactic agent.

DETAILED DESCRIPTION OF CERTAIN EMBODIMENTS OF THE INVENTION

As generally described herein, the present invention providessubstituted oxysterols useful for preventing and/or treating a broadrange of disorders, including, but not limited to, NMDA-mediateddisorders.

Compounds

In one aspect, provided herein are compounds according to Formula (A):

or a pharmaceutically acceptable salt thereof, wherein:

each of R^(1A) and R^(1B) is independently hydrogen, substituted orunsubstituted alkyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl, orR^(1A) and R^(1B), together with the carbon atom to which they areattached form a 3-8 membered ring;

n is 1 or 2;

each of R^(2A) and R^(2B) is independently hydrogen, halo, —OR^(C),alkyl, alkenyl, alkynyl, aryl, or heteroaryl, wherein R^(C) is hydrogenor alkyl, or R^(2A) and R^(2B), together with the carbon atom to whichthey are attached form an oxo group, wherein R^(2A) and R^(2B) are notboth simultaneously hydrogen;

R³ is hydrogen, alkyl, alkenyl, alkynyl, or —OR^(A), wherein R^(A) isalkyl;

R⁴ is absent or hydrogen; and

represents a single or double bond, wherein when one of

is a double bond, the other

is a single bond; when both of

are single bonds, then R⁴ is hydrogen; and when one of the

is a double bond, R⁴ is absent.

In some embodiments, n is 1. In other embodiments, n is 2.

In some embodiments, when R^(1A), R³, and R⁴ are hydrogen and R^(1B) isunsubstituted isopropyl, then R^(2A) and R^(2B), together with thecarbon atom to which they are attached do not form an oxo group; andwhen R⁴ is absent, R³ is hydrogen, and R^(1A) and R^(1B) are —CH₃, thenR^(2A) is not —CH₃ and R^(2B) is not —OH.

In some embodiments, when R⁴ is absent, R^(2A) is —OH, R^(2B) ishydrogen or —CF₃, and R^(1A) and R^(1B) are —CH₃, then R³ is nothydrogen; and when R^(1A) and R^(1B) are —CH₃ and R³ is hydrogen, thenR^(2A) and R^(2B), together with the carbon atom to which they areattached do not form an oxo group.

In some embodiments, wherein the compound of Formula (A) is a compoundof Formula (A-I):

In some embodiments, the compound of Formula (A) is a compound ofFormula (A-II):

In some embodiments, the compound of Formula (A) is a compound ofFormula (A-III):

In some embodiments, the compound of Formula (A) is a compound ofFormula (A-IV), (A-V), or (A-VI):

wherein R^(2C) is hydrogen or alkyl and R³ is alkyl, alkenyl, alkynyl,or —OR^(A), wherein R^(A) is alkyl.

In some embodiments, the compound of Formula (A) is a compound ofFormula (A-VII), (A-VIII), or (A-IX):

wherein R³ is alkyl, alkenyl, alkynyl, or —OR^(A), wherein R^(A) isalkyl.

In some embodiments, the compound of Formula (A) is a compound ofFormula (A-X):

wherein R³ is alkyl, alkenyl, alkynyl, or —OR^(A), wherein R^(A) isalkyl.

In some embodiments, the compound of Formula (A) is a compound ofFormula (A-XII)

where R′ is alkyl or —OR^(A), wherein R^(A) is hydrogen or alkyl; p is0, 1, 2, 3, 4, 5, or 6; and m is 0, 1, 2, or 3.

In some embodiments, R⁴ is absent, one of R^(2A) and R^(2B) is —OH, andR³ is not hydrogen.

In some embodiments, each of R^(1A) and R^(1B) is independentlyunsubstituted or substituted alkyl (e.g., haloalkyl, alkoxyalkyl, —CH₃,—CH₂CH₃, —CH(CH₃)₂, —CF₃ or —CH₂OCH₃).

In other embodiments, each of R^(1A) and R^(1B) is independentlysubstituted alkyl (e.g., haloalkyl). In some embodiments, R^(1A) andR^(1B) is alkyl (e.g., unsubstituted or substituted alkyl (e.g., —CH₃)).In some embodiments, R^(1A) and R^(1B) are —CH₃.

In some aspects, R^(1A) is —CF₃ or —CH₂OCH₃.

In other aspects, R^(1A) is hydrogen and R^(1B) is alkyl, carbocyclyl,heterocyclyl, aryl, or heteroaryl.

In some embodiments, R^(1A) and R^(1B), together with the carbon atom towhich they are attached form a 3-8 membered ring.

In some aspects, R^(1A) is substituted alkyl or unsubstituted C₂-C₆alkyl and R^(1B) is substituted or unsubstituted C₁-C₆ alkyl.

In some embodiments, each of R^(2A) and R^(2B) is independently alkyl(e.g., substituted or unsubstituted alkyl). In some aspects, each ofR^(2A) and R^(2B) is independently —F.

In other embodiments, R^(2A) and R^(2B) are —CH₃ and R³ is alkyl,alkenyl, alkynyl, or —OR^(A), wherein R^(A) is alkyl. In some otherembodiments, each of R^(2A) and R^(2B) is independently hydrogen and R³is alkyl (e.g., substituted or unsubstituted alkyl).

In some embodiments, wherein R³ is alkyl (e.g., substituted orunsubstituted alkyl), alkenyl, alkynyl, or —OR^(A), wherein R^(A) isalkyl. In other embodiments, R³ is alkyl (e.g., substituted orunsubstituted alkyl).

In one aspect, provided herein are compounds according to Formula (B):

or a pharmaceutically acceptable salt thereof, wherein:

each of R^(1A) and R^(1B) is independently hydrogen, substituted orunsubstituted alkyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl, orR^(1A) and R^(1B), together with the carbon atom to which they areattached form a 3-8 membered ring;

n is 1 or 2;

each of R^(2A) and R^(2B) is independently hydrogen, halo, —OR^(C),alkyl, alkenyl, alkynyl, aryl, or heteroaryl, wherein R^(C) is hydrogenor alkyl, or R^(2A) and R^(2B), together with the carbon atom to whichthey are attached form an oxo group, wherein R^(2A) and R^(2B) are notboth simultaneously hydrogen;

R³ is alkyl, alkenyl, alkynyl, or —OR^(A), wherein R^(A) is alkyl;

R⁴ is absent or hydrogen; and

represents a single or double bond, wherein when one of

is a double bond, the other

is a single bond; when both of

are single bonds, then R⁴ is hydrogen; and when one of the

is a double bond, R⁴ is absent.

In some embodiments, n is 1. In other embodiments, n is 2.

In some embodiments, wherein the compound of Formula (B) is a compoundof Formula (B-I):

In some embodiments, the compound of Formula (B) is a compound ofFormula (B-II):

In some embodiments, the compound of Formula (B) is a compound ofFormula (B-III):

In some embodiments, the compound of Formula (B) is a compound ofFormula (B-IV), (B-V), or (B-VI):

wherein R^(2C) is hydrogen or alkyl and R³ is alkyl, alkenyl, alkynyl,or —OR^(A), wherein R^(A) is alkyl.

In some embodiments, the compound of Formula (B) is a compound ofFormula (B-VII), (B-VIII), or (B -IX):

wherein R³ is alkyl, alkenyl, alkynyl, or —OR^(A), wherein R^(A) isalkyl.

In some embodiments, the compound of Formula (B) is a compound ofFormula (B-X):

wherein R³ is alkyl, alkenyl, alkynyl, or —OR^(A), wherein R^(A) isalkyl.

In some embodiments, the compound of Formula (B) is a compound ofFormula (B-XII)

where R′ is alkyl or —OR^(A), wherein R^(A) is hydrogen or alkyl; p is0, 1, 2, 3, 4, 5, or 6; and m is 0, 1, 2, or 3.

In some embodiments, each of R^(1A) and R^(1B) is independentlyunsubstituted or substituted alkyl (e.g., haloalkyl, alkoxyalkyl, —CH₃,—CH₂CH₃, —CH(CH₃)₂, —CF₃ or —CH₂OCH₃).

In other embodiments, each of R^(1A) and R^(1B) is independentlysubstituted alkyl (e.g., haloalkyl). In some embodiments, R^(1A) andIt^(1B) is alkyl (e.g., unsubstituted or substituted alkyl (e.g.,—CH₃)). In some embodiments, R^(1A) and R^(1B) are —CH₃.

In some aspects, R^(1A) is —CF₃ or —CH₂OCH₃.

In other aspects, R^(1A) is hydrogen and R^(1B) is alkyl, carbocyclyl,heterocyclyl, aryl, or heteroaryl.

In some embodiments, R^(1A) and R^(1B), together with the carbon atom towhich they are attached form a 3-8 membered ring.

In some aspects, R^(1A) is substituted alkyl or unsubstituted C₂-C₆alkyl and R^(1B) is substituted or unsubstituted C₁-C₆ alkyl.

In some embodiments, each of R^(2A) and R^(2B) is independently alkyl(e.g., substituted or unsubstituted alkyl). In some aspects, each ofR^(2A) and R^(2B) is independently —F.

In other embodiments, R^(2A) and R^(2B) are —CH₃ and R³ is alkyl,alkenyl, alkynyl, or —OR^(A), wherein R^(A) is alkyl. In some otherembodiments, each of R^(2A) and R^(2B) is independently hydrogen and R³is alkyl (e.g., substituted or unsubstituted alkyl).

In some embodiments, wherein R³ is alkyl (e.g., substituted orunsubstituted alkyl), alkenyl, alkynyl, or —OR^(A), wherein R^(A) isalkyl. In other embodiments, R³ is alkyl (e.g., substituted orunsubstituted alkyl).

In one aspect, provided herein are compounds according to Formula (I):

or a pharmaceutically acceptable salt thereof, wherein:

each of R^(1A) and R^(1B) is independently hydrogen, substituted orunsubstituted alkyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl, orR^(1A) and R^(1B), together with the carbon atom to which they areattached forms a 3-8 membered ring; each of R^(2A) and R^(2B) isindependently hydrogen, halo, —OR^(C), alkyl, alkenyl, alkynyl, aryl, orheteroaryl, wherein R^(C) is hydrogen or alkyl, or R^(2A) and R^(2B),together with the carbon atom to which they are attached form an oxogroup, wherein R^(2A) and R^(2B) are not both simultaneously hydrogen;R³ is hydrogen, alkyl, alkenyl, alkynyl, or —OR^(A), wherein R^(A) isalkyl; R⁴ is absent or hydrogen; and

represents a single or double bond, wherein when one of

is a double bond, the other

is a single bond; when both of

are single bonds, then R⁴ is hydrogen; and when one of the

is a double bond, R⁴ is absent; wherein when R^(1A), R³, and R⁴ arehydrogen and R^(1B) is unsubstituted isopropyl, then R^(2A) and R^(2B),together with the carbon atom to which they are attached do not form anoxo group; and when R⁴ is absent, R³ is hydrogen, and R^(1A) and R^(1B)are —CH₃, then R^(2A) is not —CH₃ and R^(2B) is not —OH.

In some embodiments, R^(1A,) R^(3,) and R⁴ are hydrogen, R^(1B) isunsubstituted isopropyl, and R^(2A) and R^(2B), together with the carbonatom to which they are attached do not form an oxo group.

In some embodiments, R⁴ is absent, R³ is hydrogen, R^(1A) and R^(1B) are—CH₃, R^(2A) is not —CH₃, and R^(2B) is not —OH.

In some embodiments, wherein the compound of Formula (I) is a compoundof Formula (I-A):

In some embodiments, the compound of Formula (I) is a compound ofFormula (I-B):

In some embodiments, the compound of Formula (I) is a compound ofFormula (I-C):

In some embodiments, the compound of Formula (I) is a compound ofFormula (I-E), (I-F), or (I-G):

wherein R^(2C) is hydrogen or alkyl and R³ is alkyl, alkenyl, alkynyl,or —OR^(A), wherein R^(A) is alkyl.

In some embodiments, the compound of Formula (I) is a compound ofFormula (I-H), (I-I), or (I-J):

wherein R³ is alkyl, alkenyl, alkynyl, or —OR^(A), wherein R^(A) isalkyl.

In some embodiments, the compound of Formula (I) is a compound ofFormula (I-K):

wherein R³ is alkyl, alkenyl, alkynyl, or —OR^(A), wherein R^(A) isalkyl.

In some embodiments, the compound of Formula (I) is a compound ofFormula (I-M):

where R′ is alkyl or —OR^(A), wherein R^(A) is hydrogen or alkyl; p is0, 1, 2, 3, 4, 5, or 6; and m is 0, 1, 2, or 3.

In some embodiments, each of R^(1A) and R^(1B) is independentlyunsubstituted or substituted alkyl (e.g., substituted or unsubstituted,—CH₃, —CH₂CH₃, —CH(CH₃)₂, —CF₃ or —CH₂OCH₃).

In some embodiments, each of R^(1A) and R^(1B) is independentlysubstituted alkyl (e.g., haloalkyl).

In some embodiments, R^(1A) is —CF₃ or —CH₂OCH₃.

In some embodiments, R^(1A) and R^(1B) is alkyl (e.g., unsubstituted orsubstituted alkyl (e.g., —CH₃)).

In some embodiments, R^(1A) and R^(1B) are —CH₃.

In some embodiments, R^(1A) and R^(1B), together with the carbon atom towhich they are attached form a 3-8 membered ring.

In some embodiments, R^(1A) is hydrogen and R^(1B) is alkyl,carbocyclyl, heterocyclyl, aryl, or heteroaryl.

In some embodiments, R^(1A) is substituted alkyl or unsubstituted C₂-C₆alkyl and R^(1B) is substituted or unsubstituted C₁-C₆ alkyl.

In some embodiments, each of R^(2A) and R^(2B) is independently alkyl(e.g., substituted or unsubstituted alkyl).

In some embodiments, each of R^(2A) and R^(2B) is independently —F.

In some embodiments, R^(2A) and R^(2B) are —CH₃ and R³ is alkyl,alkenyl, alkynyl, or —OR^(A), wherein R^(A) is alkyl.

In some embodiments, R^(2A) and R^(2B) are —F.

In some embodiments, R³ is alkyl (e.g., substituted or unsubstitutedalkyl), alkenyl, alkynyl, or —OR^(A), wherein R^(A) is alkyl.

In some embodiments, R³ is alkyl (e.g., substituted or unsubstitutedalkyl).

In some embodiments, each of R^(2A) and R^(2B) is independently hydrogenand R³ is alkyl (e.g., substituted or unsubstituted alkyl).

In one aspect, provided herein are compounds according to Formula (II):

or a pharmaceutically acceptable salt thereof, wherein:

each of R^(1A) and R^(1B) is independently hydrogen, substituted orunsubstituted alkyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl, orR^(1A) and R^(1B), together with the carbon atom to which they areattached form a 3-8 membered ring;

each of R^(2A) and R^(2B) is independently hydrogen, halo, —OR^(C),alkyl, alkenyl, alkynyl, aryl, or heteroaryl, wherein R^(C) is hydrogenor alkyl, or R^(2A) and R^(2B), together with the carbon atom to whichthey are attached form an oxo group, wherein R^(2A) and R^(2B) are notboth simultaneously hydrogen;

R³ is hydrogen, alkyl, alkenyl, alkynyl, or —OR^(A), wherein R^(A) isalkyl;

R⁴ is absent or hydrogen; and

represents a single or double bond, wherein when one of

is a double bond, the other

is a single bond; when both of

are single bonds, then R⁴ is hydrogen; and when one of the

is a double bond, R⁴ is absent;

provided that when R⁴ is absent, R^(2A) is —OH, R^(2B) is hydrogen or—CF₃, and R^(1A) and R^(1B) are —CH₃, then R³ is not hydrogen; and whenR^(1A) and R^(1B) are —CH₃ and R³ is hydrogen, then R^(2A) and R^(2B),together with the carbon atom to which they are attached do not form anoxo group.

In some embodiments, R⁴ is absent, one of R^(2A) and R^(2B) is —OH, andR³ is not hydrogen.

In some embodiments, the compound of Formula (II) is a compound ofFormula (II-A):

In some embodiments, the compound of Formula (II) is a compound ofFormula (II-B):

In some embodiments, the compound of Formula (II) is a compound ofFormula (II-C):

In some embodiments, the compound of Formula (II) is a compound ofFormula (II-D):

In some embodiments, the compound of Formula (II) is a compound ofFormula (II-E), (II-F), or (II-G):

wherein R^(2C) is hydrogen or alkyl (e.g., substituted or unsubstitutedalkyl) and R³ is alkyl (e.g., substituted or unsubstituted alkyl).

In some embodiments, the compound of Formula (II) is a compound ofFormula (II-H), (II-I), or (II-J):

wherein R³ is alkyl, alkenyl, alkynyl, or —OR^(A), wherein R^(A) isalkyl.

In some embodiments, the compound of Formula (II) is a compound ofFormula (II-K):

where R′ is alkyl or —OR^(A), wherein R^(A) is hydrogen or alkyl; p is0, 1, 2, 3, 4, 5, or 6; and m is 0, 1, 2, or 3.

In some embodiments, each of R^(1A) and R^(1B) is independentlyunsubstituted or substituted alkyl (e.g., haloalkyl, alkoxyalkyl, —CH₃,—CH₂CH₃, —CH(CH₃)₂, —CF₃ or —CH₂OCH₃).

In some embodiments, each of R^(1A) and R^(1B) is independentlysubstituted alkyl (e.g., haloalkyl).

In some embodiments, R^(1A) is —CF₃ or —CH₂OCH₃.

In some embodiments, R^(1A) and R^(1B) is alkyl (e.g., unsubstituted orsubstituted alkyl (e.g., —CH₃)).

In some embodiments, R^(1A) and R^(1B) are —CH₃.

In some embodiments, R^(1A) and R^(1B), together with the carbon atom towhich they are attached form a ring.

In some embodiments, R^(1A) is hydrogen and R^(1B) is alkyl,carbocyclyl, heterocyclyl, aryl, or heteroaryl.

In some embodiments, each of R^(2A) and R^(2B) is independently alkyl(e.g., substituted or unsubstituted alkyl).

In some embodiments, R³ is alkyl (e.g., substituted or unsubstitutedalkyl).

In some embodiments, each of R^(2A) and R^(2B) is independently hydrogenand R³ is alkyl (e.g., substituted or unsubstituted alkyl).

In some embodiments, each of R^(2A) and R^(2B) is independently —F.

In some embodiments, R^(2A) and R^(2B) are —CH₃ and R³ is alkyl,alkenyl, alkynyl, or —OR^(A), wherein R^(A) is alkyl.

In some embodiments, R^(2A) and R^(2B) are —F.

In some embodiments, R^(1A) is substituted alkyl or unsubstituted C₂-C₆alkyl and R^(1B) is substituted or unsubstituted C₁-C₆ alkyl.

In some aspects, the compound is a compound of Formula (III):

or a pharmaceutically acceptable salt thereof, wherein:

each of R^(1A) and R^(1B) is alkyl;

each of R^(2A) and R^(2B) is independently hydrogen, —OR^(C), or alkyl,wherein R^(C) is hydrogen or alkyl, or

R^(2A) and R^(2B), together with the carbon atom to which they areattached form an oxo group, wherein R^(2A) and R^(2B) are not bothsimultaneously hydrogen;

R³ is alkyl;

R⁴ is absent or hydrogen; and

represents a single or double bond, wherein when one of

is a double bond, the other

is a single bond; when both of

are single bonds, then R⁴ is hydrogen; and when one of the

is a double bond, R⁴ is absent.

In some aspects, R^(1A) and R^(1B) are each —CH₃.

In some aspects, R^(2A) and R^(2B) together with the carbon atom towhich they are attached form an oxo group.

In some aspects, R³ is —CH₂CH₃.

In some aspects, R^(2A) is —OH and R^(2B) is H.

In some aspects, R^(2A) is —CH₃ and R^(2B) is H.

In some aspects, R^(2A) is —OH and R^(2B) is —CH₃.

In some aspects, R^(1A) is —CF₃.

In an alternative embodiment, compounds described herein may alsocomprise one or more isotopic substitutions. For example, hydrogen maybe ²H (D or deuterium) or ³H (T or tritium); carbon may be, for example,¹³C or ¹⁴C; oxygen may be, for example, ¹⁸O; nitrogen may be, forexample, ¹⁵N, and the like. In other embodiments, a particular isotope(e.g., ³H, ¹³C, ¹⁴C, ¹⁸O, or ¹⁵N) can represent at least 1%, at least5%, at least 10%, at least 15%, at least 20%, at least 25%, at least30%, at least 35%, at least 40%, at least 45%, at least 50%, at least60%, at least 65%, at least 70%, at least 75%, at least 80%, at least85%, at least 90%, at least 95%, at least 99%, or at least 99.9% of thetotal isotopic abundance of an element that occupies a specific site ofthe compound.

Pharmaceutical Compositions

In another aspect, the invention provides a pharmaceutical compositioncomprising a pharmaceutically acceptable carrier and an effective amountof a compound of Formula (A), Formula (B), Formula (I), Formula (II), orFormula (III).

When employed as pharmaceuticals, the compounds provided herein aretypically administered in the form of a pharmaceutical composition. Suchcompositions can be prepared in a manner well known in thepharmaceutical art and comprise at least one active compound.

In one embodiment, with respect to the pharmaceutical composition, thecarrier is a parenteral carrier, oral or topical carrier.

The present invention also relates to a compound of Formula (A), Formula(B), Formula (I), Formula (II), or Formula (III) or pharmaceuticalcomposition thereof for use as a pharmaceutical or a medicament.

Generally, the compounds provided herein are administered in atherapeutically effective amount. The amount of the compound actuallyadministered will typically be determined by a physician, in the lightof the relevant circumstances, including the condition to be treated,the chosen route of administration, the actual compound administered,the age, weight, and response of the individual patient, the severity ofthe patient's symptoms, and the like.

The pharmaceutical compositions provided herein can be administered by avariety of routes including oral, rectal, transdermal, subcutaneous,intravenous, intramuscular, and intranasal. Depending on the intendedroute of delivery, the compounds provided herein are preferablyformulated as either injectable or oral compositions or as salves, aslotions or as patches all for transdermal administration.

The compositions for oral administration can take the form of bulkliquid solutions or suspensions, or bulk powders. More commonly,however, the compositions are presented in unit dosage forms tofacilitate accurate dosing. The term “unit dosage forms” refers tophysically discrete units suitable as unitary dosages for human subjectsand other mammals, each unit containing a predetermined quantity ofactive material calculated to produce the desired therapeutic effect, inassociation with a suitable pharmaceutical excipient. Typical unitdosage forms include prefilled, premeasured ampules or syringes of theliquid compositions or pills, tablets, capsules or the like in the caseof solid compositions. In such compositions, the compound is usually aminor component (from about 0.1 to about 50% by weight or preferablyfrom about 1 to about 40% by weight) with the remainder being variousvehicles or carriers and processing aids helpful for forming the desireddosing form.

Liquid forms suitable for oral administration may include a suitableaqueous or nonaqueous vehicle with buffers, suspending and dispensingagents, colorants, flavors and the like. Solid forms may include, forexample, any of the following ingredients, or compounds of a similarnature: a binder such as microcrystalline cellulose, gum tragacanth orgelatin; an excipient such as starch or lactose, a disintegrating agentsuch as alginic acid, Primogel, or corn starch; a lubricant such asmagnesium stearate; a glidant such as colloidal silicon dioxide; asweetening agent such as sucrose or saccharin; or a flavoring agent suchas peppermint, methyl salicylate, or orange flavoring.

Injectable compositions are typically based upon injectable sterilesaline or phosphate-buffered saline or other injectable carriers knownin the art. As before, the active compound in such compositions istypically a minor component, often being from about 0.05 to 10% byweight with the remainder being the injectable carrier and the like.

Transdermal compositions are typically formulated as a topical ointmentor cream containing the active ingredient(s), generally in an amountranging from about 0.01 to about 20% by weight, preferably from about0.1 to about 20% by weight, preferably from about 0.1 to about 10% byweight, and more preferably from about 0.5 to about 15% by weight. Whenformulated as an ointment, the active ingredients will typically becombined with either a paraffinic or a water-miscible ointment base.Alternatively, the active ingredients may be formulated in a cream with,for example an oil-in-water cream base. Such transdermal formulationsare well-known in the art and generally include additional ingredientsto enhance the dermal penetration of stability of the active ingredientsor the formulation. All such known transdermal formulations andingredients are included within the scope provided herein.

The compounds provided herein can also be administered by a transdermaldevice. Accordingly, transdermal administration can be accomplishedusing a patch either of the reservoir or porous membrane type, or of asolid matrix variety.

The above-described components for orally administrable, injectable ortopically administrable compositions are merely representative. Othermaterials as well as processing techniques and the like are set forth inPart 8 of Remington's Pharmaceutical Sciences, 17th edition, 1985, MackPublishing Company, Easton, Pa., which is incorporated herein byreference.

The above-described components for orally administrable, injectable, ortopically administrable compositions are merely representative. Othermaterials as well as processing techniques and the like are set forth inPart 8 of Remington's The Science and Practice of Pharmacy, 21stedition, 2005, Publisher: Lippincott Williams & Wilkins, which isincorporated herein by reference.

The compounds of this invention can also be administered in sustainedrelease forms or from sustained release drug delivery systems. Adescription of representative sustained release materials can be foundin Remington's Pharmaceutical Sciences.

The present invention also relates to the pharmaceutically acceptableformulations of a compound of Formula (A), Formula (B), Formula (I),Formula (II), or Formula (III). In one embodiment, the formulationcomprises water. In another embodiment, the formulation comprises acyclodextrin derivative. The most common cyclodextrins are α-, β- andγ-cyclodextrins consisting of 6, 7 and 8 α-1, 4-linked glucose units,respectively, optionally comprising one or more substituents on thelinked sugar moieties, which include, but are not limited to,methylated, hydroxyalkylated, acylated, and sulfoalkylethersubstitution. In certain embodiments, the cyclodextrin is a sulfoalkylether β-cyclodextrin, e.g., for example, sulfobutyl etherβ-cyclodextrin, also known as Captisol®. See, e.g., U .S. Pat. No.5,376,645. In certain embodiments, the formulation compriseshexapropyl-β-cyclodextrin. In a more particular embodiment, theformulation comprises hexapropyl-β-cyclodextrin (10-50% in water).

The present invention also relates to the pharmaceutically acceptableacid addition salt of a compound of Formula (A), Formula (B), Formula(I), Formula (II), or Formula (III). The acid which may be used toprepare the pharmaceutically acceptable salt is that which forms anon-toxic acid addition salt, i.e., a salt containing pharmacologicallyacceptable anions such as the hydrochloride, hydroiodide, hydrobromide,nitrate, sulfate, bisulfate, phosphate, acetate, lactate, citrate,tartrate, succinate, maleate, fumarate, benzoate, para-toluenesulfonate,and the like.

The following formulation examples illustrate representativepharmaceutical compositions that may be prepared in accordance with thisinvention. The present invention, however, is not limited to thefollowing pharmaceutical compositions.

Exemplary Formulation 1—Tablets: A compound of Formula (A), Formula (B),Formula (I), Formula (II), or Formula (III), or pharmaceuticallyacceptable salt thereof, may be admixed as a dry powder with a drygelatin binder in an approximate 1:2 weight ratio. A minor amount ofmagnesium stearate is added as a lubricant. The mixture is formed into240-270 mg tablets (80-90 mg of active compound per tablet) in a tabletpress.

Exemplary Formulation 2—Capsules: A compound of Formula (A), Formula(B), Formula (I), Formula (II), or Formula (III), or pharmaceuticallyacceptable salt thereof, may be admixed as a dry powder with a starchdiluent in an approximate 1:1 weight ratio. The mixture is filled into250 mg capsules (125 mg of active compound per capsule).

Exemplary Formulation 3—Liquid: A compound of Formula (A), Formula (B),Formula (I), Formula (II), or Formula (III), or pharmaceuticallyacceptable salt thereof, (125 mg) may be admixed with sucrose (1.75 g)and xanthan gum (4 mg) and the resultant mixture may be blended, passedthrough a No. 10 mesh U.S. sieve, and then mixed with a previously madesolution of microcrystalline cellulose and sodium carboxymethylcellulose (11:89, 50 mg) in water. Sodium benzoate (10 mg), flavor, andcolor are diluted with water and added with stirring. Sufficient watermay then be added to produce a total volume of 5 mL.

Exemplary Formulation 4—Tablets: A compound of Formula (A), Formula (B),Formula (I), Formula (II), or Formula (III), or pharmaceuticallyacceptable salt thereof, may be admixed as a dry powder with a drygelatin binder in an approximate 1:2 weight ratio. A minor amount ofmagnesium stearate is added as a lubricant. The mixture is formed into450-900 mg tablets (150-300 mg of active compound) in a tablet press.

Exemplary Formulation 5—Injection: A compound of Formula (A), Formula(B), Formula (I), Formula (II), or Formula (III), or pharmaceuticallyacceptable salt thereof, may be dissolved or suspended in a bufferedsterile saline injectable aqueous medium to a concentration ofapproximately 5 mg/mL.

Exemplary Formulation 6—Tablets: A compound of Formula (A), Formula (B),Formula (I), Formula (II), or Formula (III), or pharmaceuticallyacceptable salt thereof, may be admixed as a dry powder with a drygelatin binder in an approximate 1:2 weight ratio. A minor amount ofmagnesium stearate is added as a lubricant. The mixture is formed into90-150 mg tablets (30-50 mg of active compound per tablet) in a tabletpress.

Exemplary Formulation 7—Tablets: A compound of Formula (A), Formula (B),Formula (I), Formula (II), or Formula (III), or pharmaceuticallyacceptable salt thereof, may be may be admixed as a dry powder with adry gelatin binder in an approximate 1:2 weight ratio. A minor amount ofmagnesium stearate is added as a lubricant. The mixture is formed into30-90 mg tablets (10-30 mg of active compound per tablet) in a tabletpress.

Exemplary Formulation 8—Tablets: A compound of Formula (A), Formula (B),Formula (I), Formula (II), or Formula (III), or pharmaceuticallyacceptable salt thereof, may be admixed as a dry powder with a drygelatin binder in an approximate 1:2 weight ratio. A minor amount ofmagnesium stearate is added as a lubricant. The mixture is formed into0.3-30 mg tablets (0.1-10 mg of active compound per tablet) in a tabletpress.

Exemplary Formulation 9—Tablets: A compound of Formula (A), Formula (B),Formula (I), Formula (II), or Formula (III), or pharmaceuticallyacceptable salt thereof, may be admixed as a dry powder with a drygelatin binder in an approximate 1:2 weight ratio. A minor amount ofmagnesium stearate is added as a lubricant. The mixture is formed into150-240 mg tablets (50-80 mg of active compound per tablet) in a tabletpress.

Exemplary Formulation 10—Tablets: A compound of Formula (A), Formula(B), Formula (I), Formula (II), or Formula (III), or pharmaceuticallyacceptable salt thereof, may be admixed as a dry powder with a drygelatin binder in an approximate 1:2 weight ratio. A minor amount ofmagnesium stearate is added as a lubricant. The mixture is formed into270-450 mg tablets (90-150 mg of active compound per tablet) in a tabletpress.

Injection dose levels range from about 0.1 mg/kg/hour to at least 10mg/kg/hour, all for from about 1 to about 120 hours and especially 24 to96 hours. A preloading bolus of from about 0.1 mg/kg to about 10 mg/kgor more may also be administered to achieve adequate steady statelevels. The maximum total dose is not expected to exceed about 2 g/dayfor a 40 to 80 kg human patient.

For the prevention and/or treatment of long-term conditions the regimenfor treatment usually stretches over many months or years so oral dosingis preferred for patient convenience and tolerance. With oral dosing,one to five and especially two to four and typically three oral dosesper day are representative regimens. Using these dosing patterns, eachdose provides from about 0.01 to about 20 mg/kg of the compound providedherein, with preferred doses each providing from about 0.1 to about 10mg/kg, and especially about 1 to about 5 mg/kg.

Transdermal doses are generally selected to provide similar or lowerblood levels than are achieved using injection doses.

When used to prevent the onset of a CNS-disorder, the compounds providedherein will be administered to a subject at risk for developing thecondition, typically on the advice and under the supervision of aphysician, at the dosage levels described above. Subjects at risk fordeveloping a particular condition generally include those that have afamily history of the condition, or those who have been identified bygenetic testing or screening to be particularly susceptible todeveloping the condition.

Methods of Treatment and Use

Compounds of the present invention, e.g., a compound of Formula (A),Formula (B), Formula (I), Formula (II), or Formula (III), andpharmaceutically acceptable salts thereof, as described herein, aregenerally designed to modulate NMDA function, and therefore to act asoxysterols for the treatment and prevention of, e.g., CNSrelatedconditions in a subject. In some embodiments, the compounds describedherein, e.g., a compound of Formula (A), Formula (B), Formula (I),Formula (II), or Formula (III), and pharmaceutically acceptable saltsthereof, as described herein, are generally designed to penetrate theblood brain barrier (e.g., designed to be transported across the bloodbrain barrier). Modulation, as used herein, refers to, for example, theinhibition or potentiation of NMDA receptor function. In certainembodiments, the compound of Formula (A), Formula (B), Formula (I),Formula (II), or Formula (III), or pharmaceutically acceptable saltthereof, acts as a negative allosteric modulator (NAM) of NMDA, andinhibit NMDA receptor function. In certain embodiments, the presentinvention, e.g., a compound of Formula (A), Formula (B), Formula (I),Formula (II), or Formula (III), or pharmaceutically acceptable saltthereof, acts as a positive allosteric modulator (PAM) of NMDA, andpotentiate NMDA receptor function. In certain embodiments, the compoundof Formula (A), Formula (B), Formula (I), Formula (II), or Formula(III), or pharmaceutically acceptable salt thereof, blocks or reducesthe potentiation or inhibition of NMDA receptor function by anaturally-occurring substrate. Such compounds do not act as negativeallosteric modulators (NAMs) or positive allosteric modulators (PAMs) ofNMDA. In some embodiments, the disorder is cancer. In some embodiments,the disorder is diabetes. In some embodiments, the disorder is a sterolsynthesis disorder. In some embodiments, the disorder is agastrointestinal (GI) disorder, e.g., constipation, irritable bowelsyndrome (MS), inflammatory bowel disease (IBD) (e.g., ulcerativecolitis, Crohn's disease), structural disorders affecting the GI, analdisorders (e.g., hemorrhoids, internal hemorrhoids, externalhemorrhoids, anal fissures, perianal abscesses, anal fistula), colonpolyps, cancer, or colitis. In some embodiments, the disorder isinflammatory bowel disease.

Exemplary conditions related to NMDA-modulation include, but are notlimited to, gastrointestinal (GI) disorder, e.g., constipation,irritable bowel syndrome (MS), inflammatory bowel disease (IBD) (e.g.,ulcerative colitis, Crohn's disease), structural disorders affecting theGI, anal disorders (e.g., hemorrhoids, internal hemorrhoids, externalhemorrhoids, anal fissures, perianal abscesses, anal fistula), colonpolyps, cancer, colitis, and CNS conditions, e.g., as described herein.

Exemplary conditions (e.g., CNS conditions) related to NMDA-modulationinclude, but are not limited to, adjustment disorders, anxiety disorders(including obsessive-compulsive disorder, posttraumatic stress disorder,social phobia, generalized anxiety disorder), cognitive disorders(including Alzheimer's disease and other forms of dementia includingcortico-basal dementia-progressive supranucelar palsy, frontal-temoraldementia, primary progressive aphasia, Parkinson's disease dementia, andLewy body dementia), dissociative disorders, eating disorders, mooddisorders (including depression (e.g., postpartum depression), bipolardisorder, dysthymic disorder, suicidality), schizophrenia or otherpsychotic disorders (including schizoaffective disorder), sleepdisorders (including insomnia), substance abuse-related disorders,personality disorders (including obsessive-compulsive personalitydisorder), autism spectrum disorders (including those involvingmutations to the Shank group of proteins (e.g., Shank3)),neurodevelopmental disorders (including Rett syndrome), multiplesclerosis, sterol synthesis disorders, Smith-Lemli-Opitz syndrome, pain(including acute pain, chronic pain, and neuropathic pain), seizuredisorders (including status epilepticus and monogenic forms of epilepsysuch as Dravet's disease, Tuberous Sclerosis Complex (TSC), andinfantile spasms), stroke, subarachnoid hemorrhage, intracerebralhemorrhage, cerebral ischemia, traumatic brain injury, movementdisorders (including Huntington's disease and Parkinson's disease)attention deficit disorder, attention deficit hyperactivity disorder,metabolic encephalopathies (including phenylketoneuria), post-partumpsychosis, syndromes associated with high titers of anti-NMDA receptorantibodies (including anti-NMDA receptor encephalitis),neurodegenerative disorders, neuroinflammation, neuropsychiatric lupus,Niemann-Pick C disorder, and tinnitus.

In certain embodiments, compounds of the present invention, e.g., acompound of Formula (A), Formula (B), Formula (I), Formula (II), orFormula (III), or pharmaceutically acceptable salt thereof, can be usedto induce sedation or anesthesia.

In certain embodiments, the compound of Formula (A), Formula (B),Formula (I), Formula (II), or Formula (III), or pharmaceuticallyacceptable salt thereof, is useful in the treatment or prevention ofadjustment disorders, anxiety disorders (including obsessive-compulsivedisorder, posttraumatic stress disorder, social phobia, generalizedanxiety disorder), cognitive disorders (including Alzheimer's diseaseand other forms of dementia including cortico-basal dementia-progressivesupranucelar palsy, frontal-temoral dementia, primary progressiveaphasia, Parkinson's disease dementia, and Lewy body dementia),dissociative disorders, eating disorders, mood disorders (includingdepression (e.g., postpartum depression), bipolar disorder, dysthymicdisorder, suicidality), schizophrenia or other psychotic disorders(including schizoaffective disorder), sleep disorders (includinginsomnia), substance abuse-related disorders, personality disorders(including obsessive-compulsive personality disorder), autism spectrumdisorders (including those involving mutations to the Shank group ofproteins (e.g., Shank3)), neurodevelopmental disorders (including Rettsyndrome), multiple sclerosis, sterol synthesis disorders,Smith-Lemli-Opitz syndrome, pain (including acute pain, chronic pain,and neuropathic pain), seizure disorders (including status epilepticusand monogenic forms of epilepsy such as Dravet's disease, TuberousSclerosis Complex (TSC), and infantile spasms), stroke, subarachnoidhemorrhage, intracerebral hemorrhage, cerebral ischemia, traumatic braininjury, movement disorders (including Huntington's disease andParkinson's disease) attention deficit disorder, attention deficithyperactivity disorder, metabolic encephalopathies (includingphenylketoneuria), post-partum psychosis, syndromes associated with hightiters of anti-NMDA receptor antibodies (including anti-NMDA receptorencephalitis), neurodegenerative disorders, neuroinflammation,neuropsychiatric lupus, Niemann-Pick C disorder, and tinnitus.

In certain embodiments, the compound of Formula (A), Formula (B),Formula (I), Formula (II), or Formula (III), or pharmaceuticallyacceptable salt thereof, is useful in the treatment or prevention ofadjustment disorders, anxiety disorders (including obsessive-compulsivedisorder, posttraumatic stress disorder, social phobia, generalizedanxiety disorder), cognitive disorders (including Alzheimer's diseaseand other forms of dementia including cortico-basal dementia-progressivesupranucelar palsy, frontal-temoral dementia, primary progressiveaphasia, Parkinson's disease dementia, and Lewy body dementia),substance abuse-related disorders, dissociative disorders, eatingdisorders mood disorders (including depression (e.g., postpartumdepression), bipolar disorder, dysthymic disorder, suicidality),schizophrenia or other psychotic disorders (including schizoaffectivedisorder), personality disorders (including obsessive-compulsivepersonality disorder), autism spectrum disorders (including thoseinvolving mutations to the Shank group of proteins (e.g., Shank3)), orpost-partum psychosis.

In certain embodiments, the compound of Formula (A), Formula (B),Formula (I), Formula (II), or Formula (III), or pharmaceuticallyacceptable salt thereof, is useful in the treatment or prevention ofneurodevelopmental disorders (including Rett syndrome), multiplesclerosis, sterol synthesis disorders, Smith-Lemli-Opitz syndrome, pain(including acute pain, chronic pain, and neuropathic pain), seizuredisorders (including status epilepticus and monogenic forms of epilepsysuch as Dravet's disease, Tuberous Sclerosis Complex (TSC), andinfantile spasms), stroke, subarachnoid hemorrhage, intracerebralhemorrhage, cerebral ischemia, traumatic brain injury, movementdisorders (including Huntington's disease and Parkinson's disease)attention deficit disorder, attention deficit hyperactivity disorder,metabolic encephalopathies (including phenylketoneuria), syndromesassociated with high titers of anti-NMDA receptor antibodies (includinganti-NMDA receptor encephalitis), neurodegenerative disorders,neuroinflammation, neuropsychiatric lupus, Niemann-Pick C disorder, ortinnitus.

In some embodiments, a compound of the invention, e.g., a compound ofFormula (A), Formula (B), Formula (I), Formula (II), or Formula (III)that acts as a PAM of NMDA receptor function can be useful in thetreatment or prevention of conditions (e.g., CNS-related conditions)including schizophrenia or other psychotic disorders (includingschizoaffective disorder), sleep disorders (including insomnia), autismspectrum disorders (including those involving mutations to the Shankgroup of proteins (e.g., Shank3)), multiple sclerosis, movementdisorders (including Huntington's disease and Parkinson's disease),attention deficit disorder, attention deficit hyperactivity disorder,metabolic encephalopathies (including phenylketoneuria), post-partumpsychosis, and syndromes associated with high titers or anti-NMDAreceptor antibodies (including anti-NMDA receptor encephalitis).

In some embodiments, a compound of the invention, e.g., a compound ofFormula (A), Formula (B), Formula (I), Formula (II), or Formula (III),that acts as a NAM of NMDA receptor function can be useful in thetreatment or prevention of conditions (e.g., CNS-related conditions)including anxiety disorders (including obsessive-compulsive disorder,posttraumatic stress disorder, social phobia, generalized anxietydisorder), mood disorders (including depression (e.g., postpartumdepression), bipolar disorder, dysthymic disorder, suicidality),personality disorders (including obsessive-compulsive personalitydisorder), neurodevelopmental disorders (including Rett syndrome), pain(including acute and chronic pain), seizure disorders (including statusepilepticus and monogenic forms of epilepsy such as Dravet's disease,and Tuberous Sclerosis Complex (TSC)), stroke, traumatic brain injury,adjustment disorders, neuropsychiatric lupus, and tinnitus.

In some embodiments, a compound of the invention, e.g., a compound ofFormula (A), Formula (B), Formula (I), Formula (II), or Formula (III),that acts as a PAM or a NAM of NMDA receptor function can be useful inthe treatment or prevention of conditions (e.g., CNS-related conditions)including cognitive disorders (including Alzheimer's disease and otherforms of dementia including cortico-basal dementia-progressivesupranucelar palsy, frontal-temoral dementia, primary progressiveaphasia, Parkinson's disease dementia, and Lewy body dementia), sterolsynthesis disorders, and eating disorders.

In another aspect, provided is a method of treating or preventing brainexcitability in a subject susceptible to or afflicted with a conditionassociated with brain excitability, comprising administering to thesubject an effective amount of a compound of the present invention,e.g., a compound of Formula (A), Formula (B), Formula (I), Formula (II),or Formula (III), or a pharmaceutically acceptable salt thereof.

In yet another aspect, the present invention provides a combination of acompound of the present invention, e.g., a compound of Formula (A),Formula (B), Formula (I), Formula (II), or Formula (III), orpharmaceutically acceptable salt thereof, and another pharmacologicallyactive agent. The compounds provided herein can be administered as thesole active agent or they can be administered in combination with otheragents. Administration in combination can proceed by any techniqueapparent to those of skill in the art including, for example, separate,sequential, concurrent and alternating administration.

Movement Disorders

Also described herein are methods for treating a movement disorder. Asused herein, “movement disorders” refers to a variety of diseases anddisorders that are associated with hyperkinetic movement disorders andrelated abnormalities in muscle control. Exemplary movement disordersinclude, but are not limited to, Parkinson's disease and Parkinsonism(defined particularly by bradykinesia), dystonia, chorea andHuntington's disease, ataxia, tremor (e.g., essential tremor), myoclonusand startle, tics and Tourette syndrome, Restless legs syndrome, stiffperson syndrome, and gait disorders.

Tremor is an involuntary, at times rhythmic, muscle contraction andrelaxation that can involve oscillations or twitching of one or morebody parts (e.g., hands, arms, eyes, face, head, vocal folds, trunk,legs). Tremor includes hereditary, degenerative, and idiopathicdisorders such as Wilson's disease, Parkinson's disease, and essentialtremor, respectively; metabolic diseases (e.g., thyroid-parathyroid-,liver disease and hypoglycemia); peripheral neuropathies (associatedwith Charcot-Marie-Tooth, Roussy-Levy, diabetes mellitus, complexregional pain syndrome); toxins (nicotine, mercury, lead, CO, Manganese,arsenic, toluene); drug-induced (narcoleptics, tricyclics, lithium,cocaine, alcohol, adrenaline, bronchodilators, theophylline, caffeine,steroids, valproate, amiodarone, thyroid hormones, vincristine); andpsychogenic disorders. Clinical tremor can be classified intophysiologic tremor, enhanced physiologic tremor, essential tremorsyndromes (including classical essential tremor, primary orthostatictremor, and task- and position-specific tremor), dystonic tremor,parkinsonian tremor, cerebellar tremor, Holmes' tremor (i.e., rubraltremor), palatal tremor, neuropathic tremor, toxic or drug-inducedtremor, and psychogenic tremor. Other forms of tremor include cerebellartremor or intention tremor, dystonic tremor, essential tremor,orthostatic tremor, parkinsonian tremor, physiological tremor,psychogenic tremor, or rubral tremor.

Cerebellar tremor or intention tremor is a slow, broad tremor of theextremities that occurs after a purposeful movement. Cerebellar tremoris caused by lesions in or damage to the cerebellum resulting from,e.g., tumor, stroke, disease (e.g., multiple sclerosis, an inheriteddegenerative disorder).

Dystonic tremor occurs in individuals affected by dystonia, a movementdisorder in which sustained involuntary muscle contractions causetwisting and repetitive motions and/or painful and abnormal postures orpositions. Dystonic tremor may affect any muscle in the body. Dystonictremors occurs irregularly and often can be relieved by complete rest.

Essential tremor or benign essential tremor is the most common type oftremor. Essential tremor may be mild and nonprogressive in some, and maybe slowly progressive, starting on one side of the body but affect bothsides within 3 years. The hands are most often affected, but the head,voice, tongue, legs, and trunk may also be involved. Tremor frequencymay decrease as the person ages, but severity may increase. Heightenedemotion, stress, fever, physical exhaustion, or low blood sugar maytrigger tremors and/or increase their severity. Symptoms generallyevolve over time and can be both visible and persistent following onset.

Orthostatic tremor is characterized by fast (e.g., greater than 12 Hz)rhythmic muscle contractions that occurs in the legs and trunkimmediately after standing. Cramps are felt in the thighs and legs andthe patient may shake uncontrollably when asked to stand in one spot.Orthostatic tremor may occur in patients with essential tremor.

Parkinsonian tremor is caused by damage to structures within the brainthat control movement. Parkinsonian tremor is often a precursor toParkinson's disease and is typically seen as a “pill-rolling” action ofthe hands that may also affect the chin, lips, legs, and trunk. Onset ofparkinsonian tremor typically begins after age 60. Movement starts inone limb or on one side of the body and can progress to include theother side.

Physiological tremor can occur in normal individuals and have noclinical significance. It can be seen in all voluntary muscle groups.Physiological tremor can be caused by certain drugs, alcohol withdrawal,or medical conditions including an overactive thyroid and hypoglycemia.The tremor classically has a frequency of about 10 Hz.

Psychogenic tremor or hysterical tremor can occur at rest or duringpostural or kinetic movement. Patient with psychogenic tremor may have aconversion disorder or another psychiatric disease.

Rubral tremor is characterized by coarse slow tremor which can bepresent at rest, at posture, and with intention. The tremor isassociated with conditions that affect the red nucleus in the midbrain,classical unusual strokes.

Parkinson's disease affects nerve cells in the brain that producedopamine. Symptoms include muscle rigidity, tremors, and changes inspeech and gait. Parkinsonism is characterized by tremor, bradykinesia,rigidity, and postural instability. Parkinsonism shares symptoms foundin Parkinson's disease, but is a symptom complex rather than aprogressive neurodegenerative disease.

Dystonia is a movement disorder characterized by sustained orintermittent muscle contractions causing abnormal, often repetitivemovements or postures. Dystonic movements can be patterned, twisting,and may be tremulous. Dystonia is often initiated or worsened byvoluntary action and associated with overflow muscle activation.

Chorea is a neurological disorder characterized by jerky involuntarymovements typically affecting the shoulders, hips, and face.

Huntington's Disease is an inherited disease that causes nerve cells inthe brain to waste away. Symptoms include uncontrolled movements,clumsiness, and balance problems. Huntington's disease can hinder walk,talk, and swallowing.

Ataxia refers to the loss of full control of bodily movements, and mayaffect the fingers, hands, arms, legs, body, speech, and eye movements.

Myoclonus and Startle is a response to a sudden and unexpected stimulus,which can be acoustic, tactile, visual, or vestibular.

Tics are an involuntary movement usually onset suddenly, brief,repetitive, but non-rhythmical, typically imitating normal behavior andoften occurring out of a background of normal activity. Tics can beclassified as motor or vocal, motor tics associated with movements whilevocal tics associated with sound. Tics can be characterized as simple orcomplex. For example simple motor tics involve only a few musclesrestricted to a specific body part.

Tourette Syndrome is an inherited neuropsychiatric disorder with onsetin childhood, characterized by multiple motor tics and at least onevocal tic.

Restless Legs Syndrome is a neurologic sensorimotor disordercharacterized by an overwhelming urge to move the legs when at rest.

Stiff Person Syndrome is a progressive movement disorder characterizedby involuntary painful spasms and rigidity of muscles, usually involvingthe lower back and legs. Stiff-legged gait with exaggerated lumbarhyperlordosis typically results. Characteristic abnormality on EMGrecordings with continuous motor unit activity of the paraspinal axialmuscles is typically observed. Variants include “stiff-limb syndrome”producing focal stiffness typically affecting distal legs and feet.

Gait disorders refer to an abnormality in the manner or style ofwalking, which results from neuromuscular, arthritic, or other bodychanges. Gait is classified according to the system responsible forabnormal locomotion, and include hemiplegic gait, diplegic gait,neuropathic gait, myopathic gait, parkinsonian gait, choreiform gait,ataxic gait, and sensory gait.

Mood disorders

Also provided herein are methods for treating a mood disorder, forexample clinical depression, postnatal depression or postpartumdepression, perinatal depression, atypical depression, melancholicdepression, psychotic major depression, cationic depression, seasonalaffective disorder, dysthymia, double depression, depressive personalitydisorder, recurrent brief depression, minor depressive disorder, bipolardisorder or manic depressive disorder, depression caused by chronicmedical conditions, treatment-resistant depression, refractorydepression, suicidality, suicidal ideation, or suicidal behavior.

Clinical depression is also known as major depression, major depressivedisorder (MDD), severe depression, unipolar depression, unipolardisorder, and recurrent depression, and refers to a mental disordercharacterized by pervasive and persistent low mood that is accompaniedby low self-esteem and loss of interest or pleasure in normallyenjoyable activities. Some people with clinical depression have troublesleeping, lose weight, and generally feel agitated and irritable.Clinical depression affects how an individual feels, thinks, and behavesand may lead to a variety of emotional and physical problems.Individuals with clinical depression may have trouble doing day-to-dayactivities and make an individual feel as if life is not worth living.

Postnatal depression (PND) is also referred to as postpartum depression(PPD), and refers to a type of clinical depression that affects womenafter childbirth. Symptoms can include sadness, fatigue, changes insleeping and eating habits, reduced sexual desire, crying episodes,anxiety, and irritability. In some embodiments, the PND is atreatment-resistant depression (e.g., a treatment-resistant depressionas described herein). In some embodiments, the PND is refractorydepression (e.g., a refractory depression as described herein).

In some embodiments, a subject having PND also experienced depression,or a symptom of depression during pregnancy. This depression is referredto herein as) perinatal depression. In an embodiment, a subjectexperiencing perinatal depression is at increased risk of experiencingPND.

Atypical depression (AD) is characterized by mood reactivity (e.g.,paradoxical anhedonia) and positivity, significant weight gain orincreased appetite. Patients suffering from AD also may have excessivesleep or somnolence (hypersomnia), a sensation of limb heaviness, andsignificant social impairment as a consequence of hypersensitivity toperceived interpersonal rejection.

Melancholic depression is characterized by loss of pleasure (anhedonia)in most or all activities, failures to react to pleasurable stimuli,depressed mood more pronounced than that of grief or loss, excessiveweight loss, or excessive guilt.

Psychotic major depression (PMD) or psychotic depression refers to amajor depressive episode, in particular of melancholic nature, where theindividual experiences psychotic symptoms such as delusions andhallucinations.

Catatonic depression refers to major depression involving disturbancesof motor behavior and other symptoms. An individual may become mute andstuporose, and either is immobile or exhibits purposeless or bizarremovements.

Seasonal affective disorder (SAD) refers to a type of seasonaldepression wherein an individual has seasonal patterns of depressiveepisodes coming on in the fall or winter.

Dysthymia refers to a condition related to unipolar depression, wherethe same physical and cognitive problems are evident. They are not assevere and tend to last longer (e.g., at least 2 years).

Double depression refers to fairly depressed mood (dysthymia) that lastsfor at least 2 years and is punctuated by periods of major depression.

Depressive Personality Disorder (DPD) refers to a personality disorderwith depressive features.

Recurrent Brief Depression (RBD) refers to a condition in whichindividuals have depressive episodes about once per month, each episodelasting 2 weeks or less and typically less than 2-3 days.

Minor depressive disorder or minor depression refers to a depression inwhich at least 2 symptoms are present for 2 weeks.

Bipolar disorder or manic depressive disorder causes extreme mood swingsthat include emotional highs (mania or hypomania) and lows (depression).During periods of mania the individual may feel or act abnormally happy,energetic, or irritable. They often make poorly thought out decisionswith little regard to the consequences. The need for sleep is usuallyreduced. During periods of depression there may be crying, poor eyecontact with others, and a negative outlook on life. The risk of suicideamong those with the disorder is high at greater than 6% over 20 years,while self-harm occurs in 30-40%. Other mental health issues such asanxiety disorder and substance use disorder are commonly associated withbipolar disorder.

Depression caused by chronic medical conditions refers to depressioncaused by chronic medical conditions such as cancer or chronic pain,chemotherapy, chronic stress.

Treatment-resistant depression refers to a condition where theindividuals have been treated for depression, but the symptoms do notimprove. For example, antidepressants or psychological counseling(psychotherapy) do not ease depression symptoms for individuals withtreatment-resistant depression. In some cases, individuals withtreatment-resistant depression improve symptoms, but come back.Refractory depression occurs in patients suffering from depression whoare resistant to standard pharmacological treatments, includingtricyclic antidepressants, MAOIs, SSRIs, and double and triple uptakeinhibitors and/or anxiolytic drugs, as well as non-pharmacologicaltreatments (e.g., psychotherapy, electroconvulsive therapy, vagus nervestimulation and/or transcranial magnetic stimulation).

Suicidality, suicidal ideation, suicidal behavior refers to the tendencyof an individual to commit suicide. Suicidal ideation concerns thoughtsabout or an unusual preoccupation with suicide. The range of suicidalideation varies greatly, from e.g., fleeting thoughts to extensivethoughts, detailed planning, role playing, incomplete attempts. Symptomsinclude talking about suicide, getting the means to commit suicide,withdrawing from social contact, being preoccupied with death, feelingtrapped or hopeless about a situation, increasing use of alcohol ordrugs, doing risky or self-destructive things, saying goodbye to peopleas if they won't be seen again.

Symptoms of depression include persistent anxious or sad feelings,feelings of helplessness, hopelessness, pessimism, worthlessness, lowenergy, restlessness, difficulty sleeping, sleeplessness, irritability,fatigue, motor challenges, loss of interest in pleasurable activities orhobbies, loss of concentration, loss of energy, poor self-esteem,absence of positive thoughts or plans, excessive sleeping, overeating,appetite loss, insomnia, self-harm, thoughts of suicide, and suicideattempts. The presence, severity, frequency, and duration of symptomsmay vary on a case to case basis. Symptoms of depression, and relief ofthe same, may be ascertained by a physician or psychologist (e.g., by amental state examination).

Anxiety Disorders

Provided herein are methods for treating anxiety disorders. Anxietydisorder is a blanket term covering several different forms of abnormaland pathological fear and anxiety. Current psychiatric diagnosticcriteria recognize a wide variety of anxiety disorders.

Generalized anxiety disorder is a common chronic disorder characterizedby long-lasting anxiety that is not focused on any one object orsituation. Those suffering from generalized anxiety experiencenon-specific persistent fear and worry and become overly concerned witheveryday matters. Generalized anxiety disorder is the most commonanxiety disorder to affect older adults.

In panic disorder, a person suffers from brief attacks of intense terrorand apprehension, often marked by trembling, shaking, confusion,dizziness, nausea, difficulty breathing. These panic attacks, defined bythe APA as fear or discomfort that abruptly arises and peaks in lessthan ten minutes, can last for several hours and can be triggered bystress, fear, or even exercise; although the specific cause is notalways apparent. In addition to recurrent unexpected panic attacks, adiagnosis of panic disorder also requires that said attacks have chronicconsequences: either worry over the attacks' potential implications,persistent fear of future attacks, or significant changes in behaviorrelated to the attacks. Accordingly, those suffering from panic disorderexperience symptoms even outside of specific panic episodes.

Often, normal changes in heartbeat are noticed by a panic sufferer,leading them to think something is wrong with their heart or they areabout to have another panic attack. In some cases, a heightenedawareness (hypervigilance) of body functioning occurs during panicattacks, wherein any perceived physiological change is interpreted as apossible life threatening illness (i.e. extreme hypochondriasis).

Obsessive compulsive disorder is a type of anxiety disorder primarilycharacterized by repetitive obsessions (distressing, persistent, andintrusive thoughts or images) and compulsions (urges to perform specificacts or rituals). The OCD thought pattern may be likened tosuperstitions insofar as it involves a belief in a causativerelationship where, in reality, one does not exist. Often the process isentirely illogical; for example, the compulsion of walking in a certainpattern may be employed to alleviate the obsession of impending harm.And in many cases, the compulsion is entirely inexplicable, simply anurge to complete a ritual triggered by nervousness. In a minority ofcases, sufferers of OCD may only experience obsessions, with no overtcompulsions; a much smaller number of sufferers experience onlycompulsions.

The single largest category of anxiety disorders is that of phobia,which includes all cases in which fear and anxiety is triggered by aspecific stimulus or situation. Sufferers typically anticipateterrifying consequences from encountering the object of their fear,which can be anything from an animal to a location to a bodily fluid.

Post-traumatic stress disorder or PTSD is an anxiety disorder whichresults from a traumatic experience. Post-traumatic stress can resultfrom an extreme situation, such as combat, rape, hostage situations, oreven serious accident. It can also result from long term (chronic)exposure to a severe stressor, for example soldiers who endureindividual battles but cannot cope with continuous combat. Commonsymptoms include flashbacks, avoidant behaviors, and depression.

Epilepsy

Epilepsy is a brain disorder characterized by repeated seizures overtime. Types of epilepsy can include, but are not limited to generalizedepilepsy, e.g., childhood absence epilepsy, juvenile myoclonic epilepsy,epilepsy with grand-mal seizures on awakening, West syndrome,Lennox-Gastaut syndrome, partial epilepsy, e.g., temporal lobe epilepsy,frontal lobe epilepsy, benign focal epilepsy of childhood.

Epileptogenesis

Epileptogenesis is a gradual process by which a normal brain developsepilepsy (a chronic condition in which seizures occur). Epileptogenesisresults from neuronal damage precipitated by the initial insult (e.g.,status epilepticus).

Status epilepticus (SE)

Status epilepticus (SE) can include, e.g., convulsive statusepilepticus, e.g., early status epilepticus, established statusepilepticus, refractory status epilepticus, super-refractory statusepilepticus; non-convulsive status epilepticus, e.g., generalized statusepilepticus, complex partial status epilepticus; generalized periodicepileptiform discharges; and periodic lateralized epileptiformdischarges. Convulsive status epilepticus is characterized by thepresence of convulsive status epileptic seizures, and can include earlystatus epilepticus, established status epilepticus, refractory statusepilepticus, super-refractory status epilepticus. Early statusepilepticus is treated with a first line therapy. Established statusepilepticus is characterized by status epileptic seizures which persistdespite treatment with a first line therapy, and a second line therapyis administered. Refractory status epilepticus is characterized bystatus epileptic seizures which persist despite treatment with a firstline and a second line therapy, and a general anesthetic is generallyadministered. Super refractory status epilepticus is characterized bystatus epileptic seizures which persist despite treatment with a firstline therapy, a second line therapy, and a general anesthetic for 24hours or more.

Non-convulsive status epilepticus can include, e.g., focalnon-convulsive status epilepticus, e.g., complex partial non-convulsivestatus epilepticus, simple partial non-convulsive status epilepticus,subtle non-convulsive status epilepticus; generalized non-convulsivestatus epilepticus, e.g., late onset absence non-convulsive statusepilepticus, atypical absence non-convulsive status epilepticus, ortypical absence non-convulsive status epilepticus.

Seizure

A seizure is the physical findings or changes in behavior that occurafter an episode of abnormal electrical activity in the brain. The term“seizure” is often used interchangeably with “convulsion.” Convulsionsare when a person's body shakes rapidly and uncontrollably. Duringconvulsions, the person's muscles contract and relax repeatedly.

Based on the type of behavior and brain activity, seizures are dividedinto two broad categories: generalized and partial (also called local orfocal). Classifying the type of seizure helps doctors diagnose whetheror not a patient has epilepsy.

Generalized seizures are produced by electrical impulses from throughoutthe entire brain, whereas partial seizures are produced (at leastinitially) by electrical impulses in a relatively small part of thebrain. The part of the brain generating the seizures is sometimes calledthe focus.

There are six types of generalized seizures. The most common anddramatic, and therefore the most well-known, is the generalizedconvulsion, also called the grand-mal seizure. In this type of seizure,the patient loses consciousness and usually collapses. The loss ofconsciousness is followed by generalized body stiffening (called the“tonic” phase of the seizure) for 30 to 60 seconds, then by violentjerking (the “clonic” phase) for 30 to 60 seconds, after which thepatient goes into a deep sleep (the “postictal” or after-seizure phase).During grand-mal seizures, injuries and accidents may occur, such astongue biting and urinary incontinence.

Absence seizures cause a short loss of consciousness (just a fewseconds) with few or no symptoms. The patient, most often a child,typically interrupts an activity and stares blankly. These seizuresbegin and end abruptly and may occur several times a day. Patients areusually not aware that they are having a seizure, except that they maybe aware of “losing time.”

Myoclonic seizures consist of sporadic jerks, usually on both sides ofthe body. Patients sometimes describe the jerks as brief electricalshocks. When violent, these seizures may result in dropping orinvoluntarily throwing objects.

Clonic seizures are repetitive, rhythmic jerks that involve both sidesof the body at the same time.

Tonic seizures are characterized by stiffening of the muscles.

Atonic seizures consist of a sudden and general loss of muscle tone,particularly in the arms and legs, which often results in a fall.

Seizures described herein can include epileptic seizures; acuterepetitive seizures; cluster seizures; continuous seizures; unremittingseizures; prolonged seizures; recurrent seizures; status epilepticusseizures, e.g., refractory convulsive status epilepticus, non-convulsivestatus epilepticus seizures; refractory seizures; myoclonic seizures;tonic seizures; tonic-clonic seizures; simple partial seizures; complexpartial seizures; secondarily generalized seizures; atypical absenceseizures; absence seizures; atonic seizures; benign Rolandic seizures;febrile seizures; emotional seizures; focal seizures; gelastic seizures;generalized onset seizures;

infantile spasms; Jacksonian seizures; massive bilateral myoclonusseizures; multifocal seizures; neonatal onset seizures; nocturnalseizures; occipital lobe seizures; post traumatic seizures; subtleseizures; Sylvan seizures; visual reflex seizures; or withdrawalseizures. In some embodiments, the seizure is a generalized seizureassociated with Dravet Syndrome, Lennox-Gastaut Syndrome, TuberousSclerosis Complex, Rett Syndrome or PCDH19 Female Pediatric Epilepsy.

EXAMPLE 1 Synthesis of 61

Overview:

Synthesis of 1

To a mixture of MePPh₃Br (1.28 kg, 3.6 mol) in THF (4.5 L) was addedt-BuOK (404 g, 3.6 mol) at 15° C. under N₂. The resulting mixture wasstirred at 50° C. for 30 mins. Pregnenolone (950 g, 2.9 mol) was addedin portions below 65° C. The reaction mixture was stirred at 50° C. for1 hour. The combined mixture was quenched with saturated NH₄Cl aqueous(1 L) at 15° C. THF layer was separated. The aqueous was extracted withEtOAc (2×2 L). The combined organic phase was concentrated under vacuumto give a solid. The solid was further purified by trituration withMeOH/H₂O (1:1, 15 L) at reflux to give 1 (940 g, 99%) as a solid. ¹H NMR(400 MHz, CDCl₃) δ 5.40-5.32 (m, 1H), 4.85 (s, 1H), 4.71 (s, 1H),3.58-3.46 (m, 1H), 2.36-2.16 (m, 2H), 2.08-1.94 (m, 2H), 1.92-1.62 (m,9H), 1.61-1.39 (m, 6H), 1.29-1.03 (m, 4H), 1.01 (s, 3H), 0.99-0.91 (m,1H), 0.59 (s, 3H).

Synthesis of 2

To a solution of 1 (800 g, 2.54 mol) in DCM (8 L) was added DMP (2.14kg, 5.08 mol) in portions at 35° C. The reaction mixture was stirred at35° C. for 20 mins. The reaction mixture was filtered. The filtered cakewas washed with DCM (3×1 L). The combined organic phase was washed withsaturated Na₂S₂O₃/saturated NaHCO₃ aqueous (3:1, 2×1.5 L), brine (1.5L), dried over Na₂SO₄, filtered and concentrated under vacuum to give 2(794 g, crude) as a solid, which was used for next step directly.

Synthesis of 3

To a solution of BHT (1.97 kg, 8.94 mol) in toluene (1 L) was addedAlMe₃ (2.14 L, 2.0 M in toluene, 4.28 mol) drop-wise below 25° C. underN₂ atmosphere. The resulting mixture was stirred at 25° C. for 1 hour. 2(794 g, 85% percent weight, 2.16 mol) in DCM (3 L) was added at −70° C.The mixture was stirred at −70° C. for 1 hour. MeMgBr (862 mL, 3.0 M indiethyl ether, 2.59 mol) was added at −70° C. The reaction mixture wasstirred at −70° C. for 10 mins. The mixture was quenched by saturatedcritic acid (3 L), extracted with EtOAc (2×2 L). The combined organicphase was washed with brine (2 L), dried over Na₂SO₄, filtered andconcentrated under vacuum to give a residue, which was triturated fromMeCN (3 L) at 25° C. to give 3 (340 g, 43%) as a solid. ¹H NMR (400 MHz,CDCl₃) δ 5.34-5.26 (m, 1H), 4.85 (s, 1H), 4.71 (s, 1H), 2.50-2.35 (m,1H), 2.07-1.94 (m, 3H), 1.91-1.84 (m, 1H), 1.83-1.63 (m, 8H), 1.58-1.33(m, 6H), 1.27-1.13 (m, 3H), 1.12 (s, 3H), 1.10-1.05 (m, 1H), 1.02 (s,3H), 1.00-0.92 (m, 1H), 0.58 (s, 3H).

Synthesis of 4

3 (100 g, 304 mmol) was dissolved in 9-BBN (1.21 L, 0.5 M in THF, 608mmol) at 0° C. under N₂. The solution was stirred at 65° C. for 1 hourand re-cooled to 10° C. A lot of solid was precipitated. Ethanol (279 g,6080 mmol) and NaOH aqueous (304 mL, 5 M, 1520 mmol) were addeddrop-wise to the mixture below 10° C. to give a clear solution. Afterthat, hydrogen peroxide (343 g, 30% in water, 3040 mmol) was addeddrop-wise below 10° C. The reaction mixture was stirred at 75° C. for 1hour. After re-cooling to 20° C., solid was precipitated and collectedby filtration. The filter cake was washed with water (3×500 mL), driedunder vacuum to give a solid, which was triturated in ethanol (1.5 L) atreflux to give 4 (92 g, 87.6%) as a solid. ¹H NMR (400 MHz, CDCl₃) δ5.31-5.29 (m, 1H), 3.65-3.63 (m, 1H), 3.38-3.37 (m, 1H), 2.42 (d,J=12.4, 1H), 2.05-1.92 (m, 3H), 1.88-1.63 (m, 4H), 1.63-1.40 (m, 8H),1.40-0.90 (m, 16H), 0.70 (s, 3H).

Synthesis of 5

To a solution of 4 (124.5 g, 357 mmol) in chloroform (1 L) and pyridine(700 mL) was added TsCl (204 g, 1071 mmol) at 15° C. The mixture wasstirred at 15° C. for 2 hrs. The mixture was concentrated under vacuumto remove most of chloroform. The pyridine mixture was added into water(6 L). A solid was produced and collected by filtration, which waswashed with water (6×1 L). The solid was dissolved in DCM (3.5 L), driedover Na₂SO₄, filtered and concentrated under vacuum to give 5 (163 g,92%) as a solid. ¹H NMR (400 MHz, CDCl₃) δ 7.78 (d, J=8.0 Hz, 2H), 7.34(d, J=8.4 Hz, 2H), 5.29-5.28 (m, 1H), 3.96 (dd, J=3.2, 9.6 Hz, 1H), 3.79(dd, J=6.4, 9.2 Hz, 1H), 2.45 (s, 3H), 2.41 (d, J=13.6 Hz, 1H),1.99-1.91 (m, 3H), 1.77-1.39 (m, 11H), 1.26-0.86 (m, 16H), 0.64 (s, 3H).

Synthesis of 61

To a solution of 5 (163 g, 325 mmol) in DMF (1.7 L) was added KI (258 g,1560 mmol) at 15° C. The mixture was stirred at 60° C. for 2 hours.After that, sodium benzenesulfinate (195 g, 975 mmol) was added and themixture was stirred at 60° C. for 2 hours. The reaction mixture wascooled to 25° C. and combined with another batch from 83 g of 5. Thecombined mixture was poured into water (20 L) and some solid wasproduced. The mixture was filtered and the filter cake was washed withwater (3×2 L). The resulting filter cake dissolved in DCM (5 L), washedwith water (2×1 L), brine (2×1 L), dried over Na₂SO₄, filtered andconcentrated in vacuum to give a crude product as a solid, which wasre-crystallized in toluene (2.5 L) to give 61 (150 g, 65%) as a solid.The re-crystallization filtrate was concentrated under vacuum to give acrude 61 (30 g) as a solid. ¹H NMR (400 MHz, CDCl₃) δ 7.91 (d, J=7.2 Hz,2H), 7.69-7.61 (m, 1H), 7.60-7.50 (m, 2H), 5.28-5.27 (m, 1H), 3.14 (d,J=14.0 Hz, 1H), 2.85 (dd, J=9.6, 14.0 Hz, 1H), 2.41 (d, J=12.8 Hz, 1H),2.17-2.03 (m, 1H), 2.02-1.87 (m, 3H), 1.81-1.65 (m, 3H), 1.60-1.32 (m,8H), 1.25-0.85 (m, 16H), 0.65 (s, 3H). LCMS Rt=2.057 min in 3.0 minchromatography, 30-90 AB, purity 100%, MS ESI calcd. for C₂₉H₄₁O₂S[M+H−H₂O]⁺ 453, found 453.

EXAMPLE 2 Synthesis of Epoxide

To a suspension of t-BuOK (3.53 g, 31.6 mmol) in THF (30 mL) was addedMe₃SI (4.18 g, 20.5 mmol) under N₂ at 15° C. The suspension was stirredat 15° C. for 30 min. To the mixture was added a solution of 21 (2 g,15.8 mmol) in 10 ml of THF dropwise at 15° C. The mixture was stirred at15° C. for 16 hrs. The mixture was quenched with sat.NH₄Cl (100 mL) andextracted with EtOAc (3×150 mL). The combined organic phase was driedover Na₂SO₄, filtered, and concentrated in vacuum to give 22 (1.8 g,81%) as a liquid. ¹H NMR (400 MHz, CDCl₃) δ 2.58 (s, 2H), 1.90-1.80 (m,1H), 1.70-1.55 (m, 2H), 1.54-1.45 (m, 3H), 1.40-1.30 (m, 2H), 1.00-0.90(m, 6H).

EXAMPLE 3 Synthesis of 71

Overview:

Synthesis of Compound 4-2. To a solution of 4-1 (38 g, 101.5 mmol) inTHF (400 mL) at room temperature was added HATU (46.3 g, 121.8 mmol),DIPEA (45.9 g, 355.2 mmol). The mixture was stirred for 1 h, andN,O-dimethylhydroxylamine hydrochloride (19.8 g, 203 mmol) was added.The mixture was stirred at room temperature for another 6 h. Thereaction mixture was concentrated, poured into water, extracted withEtOAc, washed with water, dried over Na₂SO₄, and concentrated to givecrude product. The crude product was purified by column chromatographyon silica gel (eluent: PE: EA=3:1) to afford the desired product 4-2 (24g, 57%) as a solid.

¹H NMR: (300 MHz, CDCl3) δ: ppm 5.25 (d, J=5.2Hz, 1H), 3.59 (s, 3H),3.46-3.37 (m, 1H), 3.07 (s, 3H), 2.70 (s, 1H), 2.40-2.09 (m, 4H),1.92-1.63 (m, 6H), 1.44-1.33 (m, 6H), 1.29-1.15 (m, 3H), 1.11-0.93 (m,5H), 0.90 (s, 3H), 0.85 (d, J=6.4 Hz, 3H), 0.82-0.78 (m, 1H), 0.58 (s,3H).

Synthesis of Compound 4-3. To a solution of compound 4-2 (14 g, 33.52mmol, 1.0 eq) in dry CH₂Cl₂ (600 mL) was added Dess-Martin (28 g, 67.04mmol, 2.0 eq) in portions at 0° C. Then the reaction mixture was stirredat room temperature for 6.5 h. TLC (PE: EA=3:1) showed the startingmaterial was consumed completely. The mixture was quenched withsaturated aqueous NaHCO₃/Na₂S₂O₃=1:3 (800 mL). The organic phase waswashed with brine (500 mL) and dried over Na₂SO₄, and the solvent wasevaporated to afford crude product 4-3 (14.0 g, 100%).

Synthesis of Compound 4-4. To a solution of MAD (101 mmol, 3.0 eq) intoluene, freshly prepared by addition of a solution of Me₃Al (50.5 mL,101.00 mmol, 2 M in hexane) to a stirred solution of2,6-di-tent-butyl-4-methylphenol (44.4 g, 202 mmol) in toluene (200 mL)followed by stirring for 1 h at room temperature, was added dropwise asolution of 4-3 (14.0 g, 33.7mmo1, 1.0 eq) in toluene (10 mL) at −78° C.under nitrogen. Then the reaction mixture was stirred for 30 min, asolution of MeMgBr (33.7 mL, 101 mmol, 3.0 eq, 3 M in ether) was addeddropwise at −78° C. The reaction mixture was warmed to 25° C. andstirred at this temperature for 12 h. TLC (PE: EA=3:1) showed that thestarting material was consumed completely. The mixture was poured intoaqueous saturated NH₄Cl solution (200 mL) and extracted with EtOAc (200mL×2). The combined organic phases were dried over Na₂SO₄, and thesolvent was evaporated to afford crude product. The crude product waspurified by column chromatography on silica gel (eluent: PE: EA=3:1) togive the pure target (7.5 g, 52%) as a powder.

-   ¹H NMR: (400 MHz, CDCl3) δ 5.30 (d, J=5.2Hz, 1H), 3.69 (s, 3H), 3.17    (s, 3H), 2.50-2.30 (m, 3H), 2.05-1.70 (m, 7H), 1.52-1.30 (m, 9H),    1.20-0.90 (m, 15H), 0.68 (s, 3H).

Synthesis of Compound 3-1. To a solution of compound 4-4 (7.5 g, 17.4mmol, 1.0 eq) in THF (150 mL) was added dropwise a solution of MeMgBr(29mL, 87 mmol, 5.0 eq, 3 M in THF) at room temperature during a periodof 30 min under nitrogen. Then the reaction mixture was stirred at roomtemperature for 12 h. TLC (PE:EA=1:1) showed that the starting materialwas consumed completely. The mixture was poured into aqueous saturatedNH₄Cl solution (200 mL) and extracted with EtOAc (150 mL×2). Thecombined organic phases were dried over Na₂SO₄, and the solvent wasevaporated to afford crude product. The crude product was purified bycolumn chromatography on silica gel (eluent: PE: EA=4:1) to give theproduct 3-1 (5.2 g, 77%) as a powder.

-   ¹H NMR: (400 MHz, CDCl3) δ 5.30 (d, J=5.2Hz, 1H), 2.50-2.30 (m, 3H),    2.14 (s, 3H) 2.03-1.93 (m, 3H), 1.87-1.68 (m, 4H), 1.60-1.18 (m,    12H), 1.12 (s, 3H), 1.11-1.03 (m, 1H), 1.01 (s, 3H),1.00-0.94 (m,    1H), 0.91 (d, J=6.4Hz, 3H), 0.68 (s, 3H).

Synthesis of 3-2. To a suspension of 3-1 (400 mg, 1.035 mmol) and CsF(76 mg) in toluene/THF (20 mL, 8/1) was added TMSCF₃ (1.53 mL, 10.35mmol) and the mixture was stirred for 20° C. at room temperature undernitrogen. TLC (petroleum ether: ethyl acetate =3/1) showed the startingmaterial was consumed completely. A solution of TBAF (6.8 mL, 1 M inTHF) was added and the mixture was stirred for 4 h at room temperature.The mixture was diluted with MTBE (200 mL), washed with aq. saturatedNaHCO₃ solution (30 mL×3) and concentrated in vacuum. The residue waspurified by column chromatography on silica gel (eluent: petroleumether: ethyl acetate =20:1) to afford 3-2 (220 mg, 46%) as a solid.

-   ¹H NMR:(400 MHz, CDCl3) δ 5.31 (d, J=2.0 Hz, 1H), 2.44-2.41 (m, 1H),    2.04-1.96 (m, 3H), 1.81-1.67 (m, 5H), 1.65-1.39 (m, 11H), 1.34-1.32    (m, 3H), 1.31-1.25 (m, 1H), 1.21-1.10 (m, 3H), 1.12-0.98 (m, 4H),    0.96 (s, 3H), 0.98-0.90 (m, 4H), 0.68 (s, 3H.)

Synthesis of 71. Compound 3-2 (1.2 g, 2.63 mmol) was split by SFC to getProduct 71 (400 mg).

-   ¹H NMR (71): (400 MHz, CDCl₃) δ 5.32 (d, J=4.0 Hz, 1H), 2.50-2.40    (m, 1H), 2.08-1.95 (m, 3H), 1.90-0.90 (m, 35H), 0.70 (s, 3H).

EXAMPLE 4 Synthesis of 1201

To a solution of 001-4 (50 g, 128 mmol) in DCM (800 mL) was added DMP(108 g, 256 mmol) at 30° C. The reaction mixture was stirred at 30° C.for 10 minutes. And H₂O (2.3 g, 128 mmol) was added dropwise. Thereaction mixture was quenched with Saturated NaHCO₃ aqueous (500 mL)until pH of the aqueous layer became about 9. The mixture was filtered.The DCM layer was separated and the aqueous phase was extracted with DCM(100 mL). The combined organic phase was washed with saturated Na₂S₂O₃aqueous (600 mL), brine (500 mL), dried over Na₂SO₄, filtered andconcentrated to give 55 (108 g, crude) as an oil. The reaction wasconducted in parallel for 2 times.

-   ¹H NMR (400 MHz, CDCl₃) δ 5.30-5.26 (m, 1H), 3.67 (s, 3H), 3.30-3.22    (m, 1H), 2.85-2.79 (m, 1H), 2.50-2.15 (m, 4H), 2.08-1.96 (m, 3H),    1.90-1.71 (m, 2H), 1.56-1.45 (m, 6H), 144-1.19 (m, 3H), 1.17 (s,    3H), 1.15-0.97 (m, 5H), 0.96-0.88 (m, 3H), 0.70 (s, 3H).

To a solution of BHT (367 g, 1.67 mmol) in toluene (1000 mL) undernitrogen at 0° C. was added trimethylaluminum (2 M in toluene, 418 mL,837 mmol) dropwise. The mixture was stirred at 0° C. for 30 min and useddirectly as a solution of MAD (0.59 M in toluene) without furtherpurification. To the solution of MAD (0.59 M in toluene, 1410 mL, 837mmol) under nitrogen at −78° C. was added a solution of 55 (108 g, 279mmol) in toluene (500 mL) dropwise. The mixture was stirred at −78° C.for 30 min. EtMgBr (3 M in diethyl ether, 278 mL, 837 mmol, 3M in ether)was added dropwise. The resulting mixture was stirred at −78° C. for 1hr. The reaction mixture was poured to ice-cooled aqueous citric acid(1000 mL), extracted with EtOAc (2×500 mL). The combined organic layerwas washed with brine (500 mL), dried over anhydrous sodium sulfate,filtered and concentrated. The residue was purified by columnchromatography on silica gel (0-20% of EtOAc in PE) to give 1201 (95 g,impure) as an oil. The reaction was conducted in parallel for 2 times.

-   ¹H (400 MHz, CDCl₃) δ 5.30-5.26 (m, 1H), 3.65 (s, 3H), 2.48-2.18 (m,    4H), 2.08-1.91 (m, 2H), 1.90-1.76 (m, 4H), 1.75-1.61 (m, 4H),    1.60-1.48 (m, 5H), 1.47-1.22 (m, 5H), 1.17 (s, 1H), 1.16-1.02 (m,    3H), 1.01-0.96 (m, 2H), 0.95-0.90 (m, 1H), 0.89-0.82 (m, 4H),    0.81-0.76 (m, 2H), 0.67 (s, 3H).

EXAMPLE 5 Synthesis of U6477, U6478

Overview:

The experimental of intermediate 61 can be found Example 1 herein. Thesynthesis of the epoxide can be found in Example 2 herein.

Synthesis of 62

To THF (5 mL) was added n-BuLi (6.60 mL, 2.5 M in hexane, 16.5 mmol).Then a solution of 61 (3.00 g, 6.37 mmol) in THF (30 mL) was added at−70° C. The mixture was stirred at −70° C. for 1 h.6,6-dimethyl-1-oxaspiro[2.5]octane (1.78 g, 12.7 mmol) was added at −70°C. After stirring at −70° C. for another 1 h, the mixture was warmed to25° C. and stirred for 16 hrs and treated with NH₄Cl (50 mL, sat. aq.).The mixture was extracted with EtOAc (2×30 mL). The organic layer wasseparated, dried over Na₂SO₄, filtered and concentrated to give 62 (4.00g, crude) as a solid.

Synthesis of 63

To a solution of 62 (4.00 g, 6.54 mmol) in MeOH (200 mL) was added NiCl₂(61.5 mg, 0.654 mmol) and heated at 60° C. Mg powder (6.34 g, 261 mmol)was added in portions at 60° C. The mixture was stirred at 60° C. for 1h. The mixture was quenched with HCl (200 mL, 2 M) until the reactionbecame clear and extracted with EtOAc (3×200 mL). The combined organicphase was dried over Na₂SO₄, filtered, concentrated and purified byflash column (0-15% of EtOAc in PE) to give 63 (1.20 g, 39%) as a solid.

-   ¹H NMR 63 (400 MHz, CDCl₃) δ 5.32-5.28 (m, 1H), 2.43-2.38 (m, 1H),    2.05-1.56 (m, 9H), 1.50-1.41 (m, 8H), 1.41-1.26 (m, 5H), 1.26-0.94    (m, 15H), 0.94-0.83 (m, 12H), 0.68 (s, 3H).

Synthesis of 64

A solution of 63 (2.00 g, 4.24 mmol) in ethyl acetate (120 mL) was addedmolecular sieves (200 mg) and t-butylhydroperoxide (4.23 mL, 25.4 mmol,6 M in decane). The suspension was stirred under nitrogen atmosphere for30 min at 25° C. and manganese (III) acetate dihydrate (340 mg, 1.27mmol) was then added in one portion. The reaction mixture was stirred at25° C. for 48 hrs. The solids were filtered off and the filtrate waswashed with Na₂SO₃ (200 mL), brine (200 mL) and dried over Na₂SO₄,filtered and concentrated in vacuum. The residue was purified by silicagel chromatograph (0-15% of EtOAc in DCM) to afford 64 (1.10 g, 54%) asa solid.

-   ¹H NMR 64 (400 MHz, CDCl₃) δ 5.66 (s, 1H), 2.61-2.55 (m, 1H),    2.45-2.34 (m, 1H), 2.28-2.19 (m, 2H), 2.08-1.78 (m, 5H), 1.68-1.50    (m, 9H), 1.50-1.08 (m, 21H), 0.98-0.83 (m, 9H), 0.68 (s, 3H).

Synthesis of 65

To a solution of TMSCH₂Li (0.56 M in hexane, 9.19 mL, 5.15 mmol) inanhydrous THF (25 mL) under nitrogen at −40° C. was added a solution of64 (500 mg, 1.03 mmol) dropwise. The mixture was stirred at −40° C. for4 hrs and warmed to 20° C. gradually and stirred at 20° C. foradditional 16 hrs. The reaction mixture was quenched with saturatedNH₄Cl (20 mL), acidified with 10% HCl (8 mL) and stirred for 2 hrs. Themixture was combined with another batch (prepared from 100 mg of 64),extracted with EtOAc (3×20 mL). The combined organic layer was driedover anhydrous sodium sulfate, filtered and concentrated. The residuewas purified by column chromatography on silica gel (0˜20% of EtOAc inPE) to give 65 (220 mg, 44%) as a solid.

-   ¹H NMR 65 (400 MHz, CDCl₃) δ 5.79 (s, 1H), 4.93 (s, 1H), 4.74 (s,    1H), 2.51-2.42 (m, 1H), 2.19-2.00 (m, 4H), 1.97-1.85 (m, 1H),    1.82-1.70 (m, 2H), 1.63-1.58 (m, 2H), 1.52-1.37 (m, 12H), 1.36-1.14    (m, 11H), 1.13 (s, 3H), 1.09 (s, 3H), 0.96 (d, J=6.8 Hz, 3H), 0.93    (s, 3H), 0.87 (s, 3H), 0.71 (s, 3H).

Synthesis of 66

To a solution of 65 (220 mg, 0.455 mmol) in THF (15 mL) was added 10%Pd/C (wet, 300 mg). The mixture was degassed and purged with H₂ forthree times. The mixture was stirred under a H₂ balloon (15 psi) at 15°C. for 18 hrs. The reaction mixture was filtered through a pad ofCelite, and the pad was washed with THF (4×5 mL). The combined organicsolution was concentrate to give 66 (210 mg, crude) as a solid.

-   LCMS 66 Rt=5.692 min in 7.0 min chromatography,    30-90AB_7MIN_220&254_E, (Column: Xtimate C18 2.1*30mm,3 um; Mobile    Phase: A: water(4 L)+TFA(1.5 mL) B: acetonitrile(4L)+TFA(0.75mL);    Gradient: from 30% to 90% of B in 6 min and hold 90% for 0.5 min,    then 30% of B for 0.5 min; Flow Rate: 0.8 mL/min; wavelength: UV 220    nm, 254 nm; Oven Temp: 50° C.; MS ionization: ESI; Detector: PDA,    ELSD), purity 100%, MS ESI calcd. for C₃₃H₅₃[M+H−2H₂O]⁺ 449, found    449.-   SFC 66 Peak 1: Rt=6.184 min and Peak 2 Rt=6.969 min in 10 min    chromatography, AD_3_EtOH_DEA_5_40_25ML (“Column: Chiralpak AD-3    150×4.6mm I.D., 3 um Mobile phase: A: CO₂ B:ethanol (0.05% DEA)    Gradient: from 5% to 40% of B in 5 min and hold 40% for 2.5 min,    then 5% of B for 2.5 min Flow rate: 2.5mL/min Column temp: 35° C.”).

Synthesis of U6477, U6478

-   66 (210 mg, 0.433 mmol) was purified by SFC (Column: AD(250 mm*30    mm,5 um); Condition: 0.1%NH₃H₂O EtOH; Begin B: 40%; End B:    40%;Gradient Time(min): 100%B Hold Time(min); Flow Rate(ml/min): 60    ML/MIN; Injections: 200) to afford U6477 (peak 1, 56 mg, 27%) as    solid and U6478 (peak 2, 30 mg, 14%) as solid. The stereochemistry    at C7 was assigned based on the featured HNMR of compound 82 and    compound U6429 as a). 7-alpha-H isomer with H-6 as singlet in high    field; b) 7-beta-H isomer with H-6 as doublet in low field.

U6477

-   ¹H NMR (400 MHz, CDCl₃) δ 5.79 (s, 1H), 2.50-2.42 (m, 1H), 2.05-1.65    (m, 7H), 1.55-1.35 (m, 13H), 1.34-1.05 (m, 16H), 1.03-0.85 (m, 7H),    0.84-0.75 (m, 7H), 0.70-0.60 (m, 4H). LCMS Rt =1.490 min in 2.0 min    chromatography, 30-90AB_2_MIN_E, purity 98.839%, MS ESI calcd. for    C₃₃H₅₃[M+H−2H₂O]⁺ 449, found 449.-   SFC Rt=6.292 min in 10 min chromatography, AD_3_EtOH_DEA_5_40_25 ML,    100%de.

U6478

-   ¹H NMR (400 MHz, CDCl₃) δ 5.03 (s, 1H), 2.50-2.42 (m, 1H), 2.05-1.95    (m, 2H), 1.94-1.60 (m, 6H), 1.55-1.25 (m, 15H), 1.24-1.05 (m, 12H),    1.03-0.85 (m, 16H), 0.68 (s, 3H). LCMS Rt=1.568 min in 2.0 min    chromatography, 30-90AB_2MIN_E, purity 100%, MS ESI calcd. for    C₃₃H₅₃[M+H−2H₂O]⁺ 449, found 449.-   SFC Rt=7.066 min in 10 min chromatography, AD_3_EtOH_DEA_5_40_25 ML,    95%de.

EXAMPLE 6 Synthesis of U6472, U6473

Overview:

The synthesis of 71 can be found in Example 3 herein.

Synthesis of 72

A solution of 71 (4 g, 8.76 mmol) in ethyl acetate (200 mL) was addedt-butylhydroperoxide (8.74 mL, 52.5 mmol, 6 M in decane). The suspensionwas stirred under nitrogen atmosphere for 30 min and manganese (III)acetate dihydrate (702 mg, 2.62 mmol) was then added in one portion.After stirring at 30° C. for 48 hrs, the mixture was quenched withNa₂SO₃ (200 mL) and extracted with THF (2×100 mL). The combined organicwas washed with Na₂SO₃ (200 mL) , brine (200 mL), dried over Na₂SO₄,filtered and concentrated to give a residue, which was triturated withMeCN (60 mL) to give pure 72 (800 mg) as a solid.

-   ¹H NMR 72 (400 MHz, CDCl₃) δ 5.69-5.64 (m, 1H), 2.64-2.53 (m, 1H),    2.51-2.36 (m, 1H), 2.29-2.18 (m, 2H), 2.07-1.99 (m, 1H), 1.95-1.64    (m, 6H), 1.63-1.58 (m, 3H), 1.54-1.47 (m, 3H), 1.45-1.25 (m, 8H),    1.20 (s, 3H), 1.18-1.02 (m, 6H), 0.99-0.90 (m, 3H), 0.69 (s, 3H).

Synthesis of 73

To a solution of TMSCH₂Li (18.3 mL, 8.45 mmol, 0.46M in hexane) in THF(20 mL) was added dropwise a solution of 72 (800 mg, 1.69 mmol) in THF(50 mL) at −40° C. After addition, the resulting mixture was allowed towarm to 30° C. and stirred for 16 hrs. The mixture was quenched with HCl(2M, 100 mL) and extracted with EtOAc (2×80 mL). The combined organicphase was washed with sat.NaHCO₃ (100 mL), dried over Na₂SO₄, filtered,concentrated and purified by combi-flash (0-20% of EtOAc in PE) to give73 (350 mg, 44%) as a solid.

-   ¹H NMR 73 (400 MHz, CDCl₃) δ 5.81-5.76 (m, 1H), 4.95-4.89 (m, 1H),    4.77-4.70 (m, 1H), 2.50-2.41 (m, 1H), 2.18-2.06 (m, 2H), 2.04-2.00    (m, 1H), 1.94-1.68 (m, 5H), 1.55-1.47 (m, 4H), 1.44-1.37 (m, 4H),    1.32 (s, 3H), 1.30-1.11 (m, 10H), 1.09 (s, 3H), 0.99-0.94 (m, 3H),    0.89-0.81 (m, 1H), 0.71 (s, 3H).

Synthesis of 74

To a solution of 73 (350 mg, 0.746 mmol) in THF (30 mL)) was added Pd/C(350 mg, wet). The mixture was hydrogenated at 15Psi, 30° C. for 16 hrs.The mixture was filtered. The filter cake was washed with THF (2×10 mL).The combined filtration was concentrated and purified by combi-flash(0-20% of EtOAc in PE) to give pure 74 (200 mg, 57%) as a solid.

-   SFC 74-Peak 1: Rt=3.343 min and Peak 2 Rt=4.297 min in 10 min    chromatography, AD_3_EtOH_DEA_5_40_25 ML (“Column: Chiralpak AD-3    150×4.6 mm I.D., 3 um Mobile phase: A: CO2 B:methanol (0.05% DEA)    Gradient: from 5% to 40% of B in 5 min and hold 40% for 2.5 min,    then 5% of B for 2.5 min Flow rate: 2.5mL/min Column temp.: 35° C.”

Synthesis of U6472, U6473

200 mg racemic sample was separated by SFC (column: AD(250 mm*30 mm,5um), gradient: 35-35% B (A=0.05%NH₃/H₂O, B=MeOH), flow rate: 50 mL/min)to give U6472 (57 mg, 29% yield, Peak 1) and U6473 (43 mg, 22% yield,Peak 2) as a solid. The stereochemistry at C7 was assigned based on thefeatured HNIVIR of compound 82 and compound U6429 as a). 7-alpha-Hisomer with H-6 as singlet in high field; b) 7-beta-H isomer with H-6 asdoublet in low field.

U6472

-   ¹H NMR (400 MHz, CDCl₃) δ 5.35-5.30 (m, 1H), 2.49-2.39 (m, 1H),    2.06-1.90 (m, 3H), 1.87-1.66 (m, 5H), 1.56-1.40 (m, 8H), 1.35-1.24    (m, 5H), 1.18-1.06 (m, 10H), 1.01 (s, 3H), 0.97-0.91 (m, 3H),    0.86-0.79 (m, 3H), 0.68 (s, 3H).-   LCMS Rt=1.240 min in 2.0 min chromatography, 30-90AB_E, purity 100%,    MS ESI calcd. for C₂₈H₄₄F₃O [M+H−H₂O]⁺ 453, found 453.-   SFC Rt=3.357 min in 10 min chromatography, AD_3_EtOH_DEA_5_40_25 ML,    99.72%de.

U6473

-   ¹H NMR (400 MHz, CDCl₃) δ 5.06-5.00 (m, 1H), 2.42-2.34 (m, 1H),    2.03-1.95 (m, 2H), 1.87-1.65 (m, 7H), 1.56-1.35 (m, 6H), 1.34-1.26    (m, 5H), 1.22-1.03 (m, 10H), 1.00-0.91 (m, 10H), 0.69 (s, 3H).-   LCMS Rt=1.246 min in 2.0 min chromatography, 30-90AB E, purity 100%,    MS ESI calcd. for C₂₈H₄₄F₃O [M+H−H₂O]⁺ 453, found 453.-   SFC Rt=4.300 min in 10 min chromatography, AD_3_EtOH_DEA_5_40_25 ML,    99.52%de.

EXAMPLE 7 Synthesis of U6450

The synthesis of U6461 can be found in Example 11 herein.

Synthesis of 82

To a solution of U6461 (100 mg, 0.232 mmol) in THF (5 mL) was addeddropwise K-selectride (1.16 mL, 1.16 mmol 1 1M in THF) at −70° C.Afteraddition, the mixture was warmed to 0° C. and stirred at thistemperature for 1 h. The mixture was quenched with sat.NH₄Cl (20 mL) andextracted with EtOAc (3×10 mL). The combined organic phase was washedwith brine (2×20 mL), dried over Na₂SO₄, filtered and concentrated andpurified by combi-flash (0-60% of EtOAc in PE) to give 60 mg impure 82as a solid, which was used directly for the next step. Thestereochemistry at C7 was assigned according to the literature(Synthesis, 1987, 1002) compared with compound U6429 based on a).7-alpha-H isomer with H-6 as singlet in high field; b) 7-beta-H isomerwith H-6 as doublet in low field.

Synthesis of U6450

140 mg of impure 82 was separated by SFC (column: AD(250 mm*30 mm, 5um), gradient: 50-50% B (A=0.05%NH₃/H₂O, B=MeOH), flow rate: 60 mL/min)to give 82 (70 mg, 50%) as a solid.

-   ¹H NMR U6450 (400 MHz, CDCl₃) δ 5.58-5.52 (m, 1H), 3.87-3.79 (m,    1H), 2.46-2.38 (m, 1H), 2.14-1.84 (m, 3H), 1.80-1.57 (m, 4H),    1.55-1.38 (m, 9H), 1.37-1.22 (m, 4H), 1.21-1.06 (m, 12H), 1.04-0.97    (m, 4H), 0.96-0.91 (m, 3H), 0.88-0.82 (m, 3H), 0.68 (s, 3H).-   LCMS U6450 Rt=1.108 min in 2.0 min chromatography, 30-90AB_E, purity    100%, MS ESI calcd. for C₂₈H₄₅O [M+H−2H₂O]⁺ 397, found 397.

EXAMPLE 8 Synthesis of U6437, U6438

Overview:

The synthesis of U6461 can be found in Example 11 herein.

Synthesis of 91

To a solution of U6461 (300 mg, 0.696 mmol) in THF (20 mL) was addedMeLi (2.17 mL, 3.48 moml) at 0° C. under N₂. The mixture was stirred at15° C. for 10 minutes and quenched with sat.NH₄Cl (30 mL). The reactionmixture was extracted with EtOAc (3×20 mL). The combined organic phasewas washed with sat.NH₄Cl (50 mL), dried over Na₂SO₄, filtered,concentrated and purified by combi-flash (0-50% of EtOAc in PE) to give91 (250 mg, 81%) as a solid.

Synthesis of U6437, U6438

160 mg of 91 was purified by SFC(column: AD(250 mm*30 mm,5 um)),gradient: 50-50% B (A=0.05%NH₃/H₂O, B=MeOH) to give U6437 (Peak 1, 80mg, 50%) and U6438 (Peak 2, 60 mg, 38%) as a solid.

U6437

-   ¹H NMR (400 MHz, CDCl₃) δ 5.16-5.13 (m, 1H), 2.43-2.34 (m, 1H),    2.07-1.96 (m, 2H), 1.91-1.61 (m, 5H), 1.58-1.46 (m, 5H), 1.45-1.29    (m, 7H), 1.26-1.18 (m, 9H), 1.18-1.10 (m, 6H), 1.09-1.00 (m, 5H),    0.98-0.93 (m, 3H), 0.88-0.82 (m, 3H), 0.69 (s, 3H).-   LCMS Rt=1.161 min in 2.0 min chromatography, 30-90AB_E, purity 100%,    MS ESI calcd. for C₂₉H₄₇O [M+H−2H₂O]⁺ 411, found 411.-   SFC Rt=4.266 min in 8 min chromatography,    AD_ETOH(DEA)_5_40_2,8ML_8MIN (Column: Chiralpak AD-3 100×4.6 mm    I.D., 3 um Mobile phase: A: CO2 B:ethanol (0.05% DEA)-   Gradient: from 5% to 40% of B in 4.5 min and hold 40% for 2.5 min,    then 5% of B for 1 min Flow rate: 2.8 mL/min Column temperature:40°    C.), 100%de

U6438

-   ¹H NMR (400 MHz, CDCl₃) δ 5.19-5.16 (m, 1H), 2.40-2.32 (m, 1H),    2.08-1.98 (m, 2H), 1.94-1.85 (m, 2H), 1.77-1.59 (m, 4H), 1.52-1.29    (m, 13H), 1.24 (s, 3H), 1.22-1.19 (m, 6H), 1.17-1.03 (m, 6H),    0.99-0.92 (m, 6H), 0.88-0.82 (m, 3H), 0.70 (s, 3H).-   LCMS Rt=1.162 min in 2.0 min chromatography, 30-90AB_E, purity    99.5%, MS ESI calcd. for C₂₉H₄₇O [M+H−2H₂O]⁺ 411, found 411.-   SFC Rt=5.815 min in 8 min chromatography,    AD_ETOH(DEA)_5_40_2,8ML_8MIN (Column: Chiralpak AD-3 100×4.6 mm    I.D., 3 um Mobile phase: A: CO2 B:ethanol (0.05% DEA)-   Gradient: from 5% to 40% of B in 4.5min and hold 40% for 2.5 min,    then 5% of B for 1 min Flow rate: 2.8 mL/min Column temperature:40°    C.), 98%de.-   This compound structure was confirmed by X-ray.

EXAMPLE 9 Synthesis of U6410

Overview:

The synthesis of U6461 can be found in Example 11 herein.

Synthesis of U6410

To a solution of U6461 (300 mg, 0.696 mmol) in MeOH (50 mL) was addedPd(OH)₂ (600 mg, dry). The mixture was stirred at 50 Psi, 50° C. for 48hrs. The mixture was filtered, concentrated and purified by combi-flash(0-50% of EtOAc in PE) to give U6410 (35 mg, 12%) as a solid.

-   ¹H NMR (400 MHz, CDCl₃) δ 2.39-2.29 (m, 2H), 2.26-2.15 (m, 1H),    2.03-1.87 (m, 3H), 1.70-1.56 (m, 5H), 1.53-1.37 (m, 8H), 1.36-1.24    (m, 4H), 1.23-1.16 (m, 7H), 1.15-1.04 (m, 7H), 1.02-0.90 (m, 5H),    0.89-0.83 (m, 3H), 0.65 (s, 3H).-   LCMS-Rt=1.029 min in 2.0 min chromatography, 30-90AB_E, purity 100%,    MS ESI calcd. for C₂₈H₄₇O₂ [M+H−H₂O]⁺ 415, found 415.

EXAMPLE 10 Synthesis of U6408, U6409

Overview:

The synthesis of U6461 can be found in Example 11 herein.

Synthesis of 1101

To a suspension of bromo(methyl)triphenylphosphorane (1.24 g,3.48 mmo)in THF (45 mL) was added t-BuOK (389 mg, 3.48 mmol). The mixture wasstirred at 50° C. for 30 minutes under N2. Then a solution of U6461 (300mg, 0.696 mmol) in THF (5 mL) was added and the mixture was stirred at50° C. for 1 h. The mixture was quenched with sat.NH₄Cl (50 mL) andextracted with EtOAc (3×15 mL). The combined organic phase was driedover Na₂SO₄, filtered, concentrated and purified by combi-flash (0-30%of EtOAc in PE) to give desired product (72 mg, 24%) as a solid.

-   ¹H NMR (400 MHz, CDCl₃) δ 5.80-5.75 (m, 1H), 4.93 (s, 1H), 4.73 (s,    1H), 2.43-2.36 (m, 1H), 2.20-2.01 (m, 4H), 1.99-1.86 (m, 1H),    1.80-1.62 (m, 3H), 1.61-1.58 (m, 2H), 1.56-1.46 (m, 1H), 1.45-1.22    (m, 9H), 1.21-1.18 (m, 7H), 1.16-1.05 (m, 8H), 0.99-0.91 (m, 3H),    0.88-0.82 (m, 3H), 0.71 (s, 3H).

Synthesis of 1102

To a solution of 1101 (72 mg, 0.167 mmol) in THF (5 mL) was added Pd/C(wet, 150 mg). The mixture was stirred at 15° C., 15Psi for 12 hrs. Themixture was filtered, concentrated and purified by combi-flash (0-10% ofEtOAc in PE) to give impure 1102 (50 mg, 69%) as a solid.

Synthesis of U6408, U6409

50 mg of impure 1102 was separated by SFC (column: AD(250 mm*30 mm,10um), gradient: 30-30% B (A=0.05%NH₃/H₂O B=MeOH), flow rate: 60 mL/min)to give U6408 (Peak 1, 5 mg, 10%) and U6409 (Peak 2, 7 mg, 14%) as asolid. The stereochemistry at C7 was assigned based on the featured HNMRof compound 82 and compound U6429 as a). 7-alpha-H isomer with H-6 assinglet in high field; b) 7-beta-H isomer with H-6 as doublet in lowfield.

U6408

-   ¹H NMR (400 MHz, CDCl₃) δ 5.33-5.28 (m, 1H), 2.43-2.34 (m, 1H),    2.05-1.94 (m, 3H), 1.91-1.80 (m, 1H), 1.77-1.67 (m, 2H), 1.65-1.61    (m, 2H), 1.52-1.42 (m, 6H), 1.38-1.23 (m, 6H), 1.19 (s, 6H),    1.15-1.07 (m, 6H), 1.03 (s, 3H), 0.98-0.91 (m, 4H), 0.87-0.79 (m,    6H), 0.67 (s, 3H).-   LCMS Rt=1.245 min in 2.0 min chromatography, 30-90AB E, purity 100%,    MS ESI calcd. for C₂₉H₄₇ [M+H−2H₂O]⁺ 395, found 395.-   SFC Rt=4.245 min in 10 min chromatography, Column: ChiralPak AD-3    150×4.6mm I.D., 3 um Mobile phase: A: CO₂ B:Ethanol (0.05% DEA)    Gradient: from 5% to 40% of B in 5.5 min and hold 40% for 3 min,    then 5% of B for 1.5 min Flow rate: 2.5 mL/min Column    temperature:40° C., 100%de.

U6409

-   ¹H NMR (400 MHz, CDCl₃) δ 5.04-4.99 (m, 1H), 2.38-2.28 (m, 1H),    2.07-1.96 (m, 2H), 1.92-1.78 (m, 2H), 1.72-1.62 (m, 4H), 1.53-1.44    (m, 4H), 1.43-1.25 (m, 8H), 1.19 (s, 6H), 1.16-1.05 (m, 6H),    0.99-0.91 (m, 10H), 0.88-0.81 (m, 3H), 0.68 (s, 3H).-   LCMS Rt=1.253 min in 2.0 min chromatography, 30-90AB E, purity 100%,    MS ESI calcd. for C₂₉H₄₇ [M+H−2H₂O]⁺ 395, found 395.-   SFC Rt=4.967 min in 10 min chromatography, Column: ChiralPak AD-3    150×4.6 mm I.D., 3 um Mobile phase: A: CO₂ B:Ethanol (0.05% DEA)    Gradient: from 5% to 40% of B in 5.5 min and hold 40% for 3 min,    then 5% of B for 1.5 min Flow rate: 2.5 mL/min Column    temperature:40° C., 100%de.

EXAMPLE 11 Synthesis of U6461, U6429, U6479

Overview:

The synthesis of 1201 can be found in Example 4 herein.

Synthesis of 1202

To a solution of impure 1201 (14.9 g, 35.7 mmol) in THF (600 mL) wasadded dropwise MeLi (111 mL, 178 mmol, 1.6M in ether) at 0° C. Afterstirring at 15° C. for 30 minutes, the mixture was quenched withsat.NH₄Cl (500 mL) and extracted with EtOAc (3×200 mL). The combinedorganic phase was dried over Na₂SO₄, filtered and concentrated to give acrude residue, which was triturated with MeCN (300 mL) to give 11 gcrude product as a solid. The crude was recrystallized from EtOAc (300mL) to give 1202 (9 g, 80% purity, 49%) as a solid.

-   ¹H NMR 1202 (400 MHz, CDCl₃) δ 5.28-5.25 (m, 1H), 2.40-2.32 (m, 1H),    2.05-1.92 (m, 3H), 1.90-1.80 (m, 1H), 1.79-1.58 (m, 3H), 1.56-1.51    (m, 5H), 1.50-1.39 (m, 7H), 1.38-1.28 (m, 2H), 1.27-1.16 (m, 6H),    1.15-1.04 (m, 5H), 1.02 (s, 3H), 1.00-0.96 (m, 1H), 0.95-0.88 (m,    4H), 0.87-0.77 (m, 3H), 0.68 (s, 3H).

Synthesis of U6461

To a solution of 1202 (5 g, 11.9 mmol) in ethyl acetate (300 mL) wasadded molecular sieves (10 g) and t-butylhydroperoxide (11.9 mL, 71.4mmol, 6 M in decane). The suspension was stirred under nitrogenatmosphere for 30 min and manganese(III) acetate dihydrate (956 mg, 3.57mmol) was then added in one portion. The reaction mixture was stirred at15° C. for 48 hrs. The solids were filtered off. The filtrate was washedwith Na₂SO₃ (200 mL), brine (200 mL) and dried over Na₂SO₄, filtered andconcentrated in vacuum. The residue was purified by silica gelchromatograph (0-15% of EtOAc in DCM) to afford impure U6461 (2 g, 40%)as a solid, of which 100 mg was recrystallized from MeCN (30 mL) at 90°C. to give pure U6461 (34 mg, 34%) as a solid.

-   ¹H NMR (400 MHz, CDCl₃) δ 5.67-5.64 (m, 1H), 2.58-2.49 (m, 1H),    2.47-2.36 (m, 1H), 2.31-2.20 (m, 2H), 2.06-1.81 (m, 3H), 1.79-1.68    (m, 2H), 1.55-1.49 (m, 3H), 1.48-1.37 (m, 5H), 1.36-1.24 (m, 5H),    1.23-1.16 (m, 11H), 1.15-1.05 (m, 3H), 0.92-0.92 (m, 3H), 0.90-0.83    (m, 3H), 0.68 (s, 3H).-   LCMS Rt=1.059 min in 2.0 min chromatography, 30-90 AB, purity 100%,    MS ESI calcd. for C₂₈H₄₇O₃ [M+H]⁺ 431, found 431.

Synthesis of U6429

To a solution of U6461 (500 mg, 1.16 mmol) in Me0H (30 mL) was addedCeCl₃ (857 mg, 3.48 mmol). After stirring at 15° C. for 30 minutes,NaBH₄ (197 mg, 5.80 mmol) was added in portions. The reaction mixturewas stirred at 15° C. for 30 minutes. The mixture was quenched withsat.NH₄Cl (50 mL) and extracted with EtOAc (3×30 mL). The combinedorganic phase was washed with brine (2×100 mL), dried over Na₂SO₄,filtered and concentrated to give 470 mg crude product, which wasrecrystallized from MeCN (100 mL) to give U6429 (370 mg, 74%) as asolid. The stereochemistry at C7 was assigned according to literature(Synthesis, 1987, 1002) compared with compound 82 based on a). 7-alpha-Hisomer with H-6 as singlet in high field; b) 7-beta-H isomer with H-6 asdoublet in low field.

-   ¹H NMR (400 MHz, CDCl₃) δ 5.25-5.22 (m, 1H), 3.89-3.82 (m, 1H),    2.43-2.35 (m, 1H), 2.13-1.97 (m, 2H), 1.96-1.77 (m, 2H), 1.76-1.60    (m, 3H), 1.53-1.40 (m, 8H), 1.39-1.28 (m, 5H), 1.24-1.18 (m, 7H),    1.16-0.99 (m, 9H), 0.97-0.91 (m, 3H), 0.88-0.82 (m, 3H), 0.69 (s,    3H).-   LCMS Rt=0.999 min in 2.0 min chromatography, 30-90AB_E, purity 100%,    MS ESI calcd. for C₂₈H₄₅O [M+H−2H₂O]⁺ 397, found 397. This compound    structure was confirmed by X-ray.

Synthesis of U6479

To a solution of U6429 (100 mg, 0.231 mmol) in Me0H (30 mL) was addedPd(OH)₂ (200 mg, dry). The mixture was stirred at 50° C. under H₂ (50Psi) for 48 hrs. The mixture was filtered, concentrated and purified bycombi-flash (0-50% of EtOAc in PE) to give U6479 (23 mg, 23%) as asolid.

-   ¹H NMR (400 MHz, CDCl₃) δ 3.44-3.29 (m, 1H), 2.03-1.95 (m, 1H),    1.94-1.76 (m, 2H), 1.67-1.58 (m, 4H), 1.53-1.42 (m, 6H), 1.42-1.33    (m, 5H), 1.32-1.24 (m, 4H), 1.23-1.11 (m, 11H), 1.10-1.04 (m, 2H),    0.97-0.91 (m, 4H), 0.90-0.82 (m, 6H), 0.75-0.63 (m, 4H).-   LCMS Rt=1.010 min in 2.0 min chromatography, 30-90AB_E, purity 100%,    MS ESI calcd. for C₂₈H₄₅ [M+H−3H₂O]⁺ 381, found 381.

EXAMPLE 12 EC₅₀ and E_(Max) Data Automated Patch-Clamp System (QPatchHTX)

In this study, HEK 293 cells stably transfected with glutamate-activatedchannels of the GRIN1/2A subtype will be used together with submaximalNMDA concentrations (300 μM NMDA, co-application with 8 μM Glycine) toinvestigate the negative allosteric modulation of the test compounds.

Cell Culture

-   In general, cells will be passaged at a confluence of about 80%    to-90%. For electrophysiological measurements cells will be    harvested at a confluence of about 80% to 90% from sterile culture    flasks containing culture complete medium. Cells will be transferred    as suspension in PBS to the QPatch 16X or QPatch HTX system to the    centrifuge/washer directly.-   Standard Laboratory Conditions: Cells will be incubated at 37° C. in    a humidified atmosphere with 5% CO₂ (rel. humidity about 95%).-   Culture media: The cells will be continuously maintained in and    passaged in sterile culture flasks containing a 1:1 mixture of    Dulbecco's modified eagle medium and nutrient mixture F-12    (D-MEM/F-12 1×, liquid, with L-Glutamine) supplemented with 10%    fetal bovine serum, 1% Penicillin/Streptomycin solution, and 50 μM    AP-5 blocker.-   Antibiotics: The complete medium as indicated above is supplemented    with 100 μg/mL hygromycin, 15 μg/mL blasticidin and 1 μg/mL    puromycin.-   Induction of Expression: 2.5 μg/mL tetracycline is added 24 h before    start of experiments.

Dose Formulation

-   Dose levels are in terms of test compounds, as supplied. Vehicle    will be added to achieve a stock concentration of 10 mM (storage at    −10° C. to −30° C.). A further stock solutions of 1.0 mM will be    prepared in DMSO. Details of stock solution usage (thawing, dose    formulations) will be documented in the raw data. The time period of    stock solution usage will be detailed in the report.

Test Compound Concentrations

-   Dose levels are in terms of test compounds, as supplied. Vehicle    will be added to achieve a stock concentration of 10 mM (storage at    −10° C. to −30° C.). A further stock solutions of 1.0 mM will be    prepared in DMSO. Details of stock solution usage (thawing, dose    formulations) will be documented in the raw data. The time period of    stock solution usage will be detailed in the report. One test    concentration of 1.0 μM will be tested.-   All test solutions will be prepared by diluting the stock solutions    with either Mg-free bath solution only or Mg-free bath solution    containing NMDA (300 μM) and glycine (8.0 μM) shortly prior to the    electrophysiological experiments and kept at room temperature    (19° C. to 30° C.) when in use. 0.1% DMSO will be used as vehicle.-   Frequency of preparation: For each test concentration, fresh    solutions of test compounds will be prepared every day.-   Stability of dose formulation: All preparation times will be    documented in the raw data. Any observations regarding instability    of test compounds will be mentioned in the raw data.-   Storage of dose formulation: On the day of experimentation dose    formulations will be maintained at room temperature (19° C. to 30°    C.) when in use.

Bath Solutions

-   For preparing the experiments and for formation of the    giga-ohm-seal, the following standard bath solution will be used:-   Sodium Chloride: 137 mM; Potassium Chloride: 4 mM; Calcium Chloride:    1.8 mM;-   Magnesium Chloride: 1 mM; HEPES: 10 mM; D-Glucose: 10 mM; Cremophor:    0.02%; pH (NaOH): 7.4-   The 1× bath solution will be prepared by diluting 10× bath solution    without Glucose and 100× Glucose solution with water at least every    7 days. Both stock solutions have been prepared prior to the    experimental start of the present study and stored at 1° C. to 9° C.    (10x bath solution) or −10° C. to −30° (100× Glucose solution). The    batch number(s) of the bath solution(s) used in the experiments will    be documented in the raw data. When in use, the 1× bath solution    will be kept at room temperature (19° C. to 30° C.). When not in    use, the 1× bath solution will be stored at 1° C. to 9° C.-   After the giga-seal was formed the following Mg-free bath solution    will be used:-   Sodium Chloride: 137 mM; Potassium Chloride: 4 mM; Calcium Chloride;    2.8 mM; HEPES:-   10 mM; D-Glucose: 10 mM; Cremophor: 0.02%; pH (NaOH): 7.4-   This Mg-free bath solution will be prepared as a 1× solution and    stored at 1° C. to 9° C. It will be prepared freshly at least every    10 days.

Intracellular Solution

-   The 1× intracellular solution will be thawed every day out of a    frozen 1× intracellular solution, which has been prepared prior to    the experimental start of the present study, aliquoted and stored at    −10° C. to −30° C. When in use, the 1× intracellular solution will    kept at room temperature (19° C. to 30° C.). Remaining 1×    intracellular solution will be stored in the fridge (1° C. to 9°    C.). The 1× intracellular solution will include the components    outlined below:-   Potassium Chloride: 130 mM; Magnesium Chloride: 1 mM; Mg-ATP: 5 mM;    HEPES:-   10 mM; EGTA: 5 mM; pH (KOH): 7.2

Cell Treatment

-   For this study, cells will continuously be perfused with    NMDA/Glycine, Test Compound or Test Compound/NMDA/Glycin.-   In every case, at least 30-second prewash steps with a test compound    will be performed in between applications. For details see Table A    below.

Each experiment type will be analyzed in at least n=3 isolated cells.The NMDA and Glycine stock solutions will be prepared prior to theexperimental start of the present study, stored frozen (−10° C. to −30°C.) until the day of experimentation. Shortly prior to theelectrophysiological experiments, frozen stock solutions will be thawedand diluted.

-   Control: The effect of vehicle (0.1% DMSO) and    D-(−)-2-Amino-5-phosphonopentanoic acid (AP-5) (100 μM) will be    measured at three cells every second week, in order to assure    successful expression of NMDA receptors.-   The 50 mM stock solution of AP-5 has been prepared prior to the    experimental start of the present study, aliquoted and stored frozen    (−10° C. to −30° C.) until the day of experimentation. Shortly prior    to the electrophysiological experiments the frozen stock solution    will be thawed and then diluted in Mg-free bath solution containing    NMDA (300 μM) and glycine (8.0 to give a final perfusion    concentration of 100 μM.

Experimental Procedure

-   Cells are transferred as suspension in serum-free medium to the    QPatch HTX system and kept in the cell storage tank/stirrer during    experiments. All solutions applied to cells including the    intracellular solution will be maintained at room temperature    (19° C. to 30° C.).-   During the sealing process standard bath solution described above    will be used. All solutions applied to cells including the pipette    solution will be maintained at room temperature (19° C. to 30° C.).    After formation of a Gigaohm seal between the patch electrodes and    transfected individual HEK293 cells only Mg-free bath solution will    be perfused and the cell membrane will be ruptured to assure    electrical access to the cell interior (whole-cell    patch-configuration). Inward currents will be measured upon    application of 300 μM NMDA (and 8.0 μM Glycine) to patch-clamped    cells for 5 sec. During the entire experiment the cells will be    voltage-clamped at a holding potential of −80 mV.

For the analysis of test compounds, NMDA receptors will be stimulated by300 μM NMDA and 8.0 μM Glycine and test compounds described below.Thirty-second prewash steps with a test compound will be performed inbetween applications.

TABLE A Application Protocol; use dependence of test compounds Appl. #Duration (s) Application 1 4 NMDA/Glycine 2 30 Bath 3 4 NMDA/Glycine 2repetitions 4 30 1 μM Test Compound 5 4 1 μM Test Compound +NMDA/Glycine 6 repetitions 6 30 Bath 7 4 NMDA/Glycine 2 repetitions

TABLE B Application Protocol; control experiments Appl. # Duration (s)Application 1 4 NMDA/Glycine 2 30 Bath 3 4 NMDA/Glycine 2 repetitions 430 Bath 5 4 NMDA/Glycine 6 repetitions 6 30 Bath 7 4 NMDA/Glycine + 100μM AP-5 2 repetitions

The results are reported in Table 1:

TABLE 1 Compound AVG_ AVG_ AVG_ AVG_ Structure ID EC₅₀ 2A nM E_(MAX) 2A% EC₅₀2B nM E_(MAX) 2B %

U6461 >10000 32 >10000 53

U6429 >10000 62 667 109

U6479 >10000 56 1425 92

U6408 230 343 132 447

U6409 >10000 44 >10000 71

U6410 >10000 18 >10000 44

U6437 1625 178 741 213

U6438 >10000 26 >10000 15

U6450 710 98 66 111

U6477 747 160 698 86

U6478 191 170 160 127

U6472 12.99 122 22 231

U6473 >10000 26 >10000 47

Abbreviations

-   PCC: pyridinium chlorochromate; t-BuOK: potassium tert-butoxide;    9-BBN: 9-borabicyclo[3.3.1]nonane; Pd(t-Bu3P)2:    bis(tri-tert-butylphosphine)palladium(0); AcCl: acetyl chloride;    i-PrMgCl: Isopropylmagnesium chloride; TBSC1:    tert-Butyl(chloro)dimethylsilane; (i-PrO)₄Ti: titanium    tetraisopropoxide; BHT: 2,6-di-t-butyl-4-methylphenoxide; Me:    methyl; i-Pr: iso-propyl; t-Bu: tert-butyl; Ph: phenyl; Et: ethyl;    Bz: benzoyl; BzCl: benzoyl chloride; CsF: cesium fluoride; DCC:    dicyclohexylcarbodiimide; DCM: dichloromethane; DMAP:    4-dimethylaminopyridine; DMP: Dess-Martin periodinane; EtMgBr:    ethylmagnesium bromide; EtOAc: ethyl acetate; TEA: triethylamine;    AlaOH: alanine; Boc: t-butoxycarbonyl. Py: pyridine; TBAF :    tetra-n-butylammonium fluoride; THF: tetrahydrofuran; TBS: t-butyl    dim ethyl silyl ; TMS: trimethylsilyl; TMSCF₃:    (Trifluoromethyl)trimethylsilane; Ts: p-toluenesulfonyl; Bu: butyl;    Ti(OiPr)₄: tetraisopropoxytitanium; LAH: Lithium Aluminium Hydride;    LDA: lithium diisopropylamide; LiOH.H₂O: lithium hydroxide hydrates;    MAD: methyl aluminum bis(2,6-di-t-butyl-4-methylphenoxide); MeCN:    acetonitrile; NBS: N-bromosuccinimide; Na₂SO₄: sodium sulfate;    Na₂S₂O₃: sodium thiosulfate; PE: petroleum ether; MeCN:    acetonitrile; MeOH: methanol; Boc: t-butoxycarbonyl; MTBE: methyl    tert-butyl ether; K-selectride: Potassium tri(s-butyl)borohydride.

Other Embodiments

In the claims articles such as “a,” “an,” and “the” may mean one or morethan one unless indicated to the contrary or otherwise evident from thecontext. Claims or descriptions that include “or” between one or moremembers of a group are considered satisfied if one, more than one, orall of the group members are present in, employed in, or otherwiserelevant to a given product or process unless indicated to the contraryor otherwise evident from the context. The invention includesembodiments in which exactly one member of the group is present in,employed in, or otherwise relevant to a given product or process. Theinvention includes embodiments in which more than one, or all of thegroup members are present in, employed in, or otherwise relevant to agiven product or process.

Furthermore, the invention encompasses all variations, combinations, andpermutations in which one or more limitations, elements, clauses, anddescriptive terms from one or more of the listed claims is introducedinto another claim. For example, any claim that is dependent on anotherclaim can be modified to include one or more limitations found in anyother claim that is dependent on the same base claim. Where elements arepresented as lists, e.g., in Markush group format, each subgroup of theelements is also disclosed, and any element(s) can be removed from thegroup. It should it be understood that, in general, where the invention,or aspects of the invention, is/are referred to as comprising particularelements and/or features, certain embodiments of the invention oraspects of the invention consist, or consist essentially of, suchelements and/or features. For purposes of simplicity, those embodimentshave not been specifically set forth in haec verba herein. It is alsonoted that the terms “comprising” and “containing” are intended to beopen and permits the inclusion of additional elements or steps. Whereranges are given, endpoints are included. Furthermore, unless otherwiseindicated or otherwise evident from the context and understanding of oneof ordinary skill in the art, values that are expressed as ranges canassume any specific value or subrange within the stated ranges indifferent embodiments of the invention, to the tenth of the unit of thelower limit of the range, unless the context clearly dictates otherwise.

This application refers to various issued patents, published patentapplications, journal articles, and other publications, all of which areincorporated herein by reference. If there is a conflict between any ofthe incorporated references and the instant specification, thespecification shall control. In addition, any particular embodiment ofthe present invention that falls within the prior art may be explicitlyexcluded from any one or more of the claims. Because such embodimentsare deemed to be known to one of ordinary skill in the art, they may beexcluded even if the exclusion is not set forth explicitly herein. Anyparticular embodiment of the invention can be excluded from any claim,for any reason, whether or not related to the existence of prior art.

Those skilled in the art will recognize or be able to ascertain using nomore than routine experimentation many equivalents to the specificembodiments described herein. The scope of the present embodimentsdescribed herein is not intended to be limited to the above

Description, but rather is as set forth in the appended claims. Those ofordinary skill in the art will appreciate that various changes andmodifications to this description may be made without departing from thespirit or scope of the present invention, as defined in the followingclaims.

1.-67. (canceled)
 68. A method of inducing sedation or anesthesiacomprising administering to a subject an effective amount of a compoundof Formula (B):

or a pharmaceutically acceptable salt thereof, wherein: each of R^(1A)and R^(1B) is independently hydrogen, substituted or unsubstitutedalkyl, substituted or unsubstituted carbocyclyl, wherein the carbocyclylmay be saturated or partially saturated, substituted or unsubstitutedheterocyclyl, substituted or unsubstituted aryl, or substituted orunsubstituted heteroaryl, or R^(1A) and R^(1B), together with the carbonatom to which they are attached form a 3-8 membered ring; n is 1 or 2;each of R^(2A) and R^(2B) is independently hydrogen, halo, —OR^(C),substituted or unsubstituted alkyl, substituted or unsubstitutedalkenyl, substituted or unsubstituted alkynyl, substituted orunsubstituted aryl, or substituted or unsubstituted heteroaryl, whereinR^(C) is hydrogen or substituted or unsubstituted alkyl, or R^(2A) andR^(2B), together with the carbon atom to which they are attached form anoxo group, wherein R^(2A) and R^(2B) are not both simultaneouslyhydrogen; R³ is substituted or unsubstituted alkyl, substituted orunsubstituted alkenyl, substituted or unsubstituted alkynyl, or —OR^(A),wherein R^(A) is substituted or unsubstituted alkyl; R⁴ is absent orhydrogen; and

represents a single or double bond, wherein when one of

is a double bond, the other

is a single bond; when both of

are single bonds, then R⁴ is hydrogen; and when one of the

is a double bond, R⁴ is absent, or a pharmaceutical compositioncomprising said compound of Formula (B) or pharmaceutically acceptablesalt thereof, and a pharmaceutically acceptable carrier.
 69. (canceled)70. A method of treating a disorder selected from the group consistingof gastrointestinal (GI) disorder, constipation, irritable bowelsyndrome (IBS), inflammatory bowel disease (IBD), ulcerative colitis,Crohn's disease structural disorders affecting the GI, anal disorders,hemorrhoids, internal hemorrhoids, external hemorrhoids, anal fissures,perianal abscesses, anal fistula, colon polyps, cancer, and colitis,comprising administering to a subject in need thereof an effectiveamount of a compound of Formula (B):

or a pharmaceutically acceptable salt thereof, wherein: each of R^(1A)and R^(1B) is independently hydrogen, substituted or unsubstitutedalkyl, substituted or unsubstituted carbocyclyl, wherein the carbocyclylmay be saturated or partially saturated, substituted or unsubstitutedheterocyclyl, substituted or unsubstituted aryl, or substituted orunsubstituted heteroaryl, or R^(1A) and R^(1B), together with the carbonatom to which they are attached form a 3-8 membered ring; n is 1 or 2;each of R^(2A) and R^(2B) is independently hydrogen, halo, —OR^(C),substituted or unsubstituted alkyl, substituted or unsubstitutedalkenyl, substituted or unsubstituted alkynyl, substituted orunsubstituted aryl, or substituted or unsubstituted heteroaryl, whereinR^(C) is hydrogen or substituted or unsubstituted alkyl, or R^(2A) andR^(2B), together with the carbon atom to which they are attached form anoxo group, wherein R^(2A) and R^(2B) are not both simultaneouslyhydrogen; R³ is substituted or unsubstituted alkyl, substituted orunsubstituted alkenyl, substituted or unsubstituted alkynyl, or —OR^(A),wherein R^(A) is substituted or unsubstituted alkyl; R⁴ is absent orhydrogen; and

represents a single or double bond, wherein when one of

is a double bond, the other

is a single bond; when both of

are single bonds, then R⁴ is hydrogen; and when one of the

is a double bond, R⁴ is absent or a pharmaceutical compositioncomprising said compound of Formula (B) or pharmaceutically acceptablesalt thereof, and a pharmaceutically acceptable carrier. 71.-76.(canceled)
 77. A method of treating a CNS-related condition selectedfrom the group consisting of an adjustment disorder, anxiety disorder,cognitive disorder, dissociative disorder, eating disorder, mooddisorder, schizophrenia or other psychotic disorder, sleep disorder,substance-related disorder, personality disorder, autism spectrumdisorders, neurodevelopmental disorder, multiple sclerosis, sterolsynthesis disorders, pain, encephalopathy secondary to a medicalcondition, seizure disorder, stroke, traumatic brain injury, movementdisorder, vision impairment, hearing loss, or tinnitus, comprisingadministering to a subject in need thereof an effective amount of acompound of Formula (B):

or a pharmaceutically acceptable salt thereof, wherein: each of R^(1A)and R^(1B) is independently hydrogen, substituted or unsubstitutedalkyl, substituted or unsubstituted carbocyclyl, wherein the carbocyclylmay be saturated or partially saturated, substituted or unsubstitutedheterocyclyl, substituted or unsubstituted aryl, or substituted orunsubstituted heteroaryl, or R^(1A) and R^(1B), together with the carbonatom to which they are attached form a 3-8 membered ring; n is 1 or 2;each of R^(2A) and R^(2B) is independently hydrogen, halo, —OR^(C),substituted or unsubstituted alkyl, substituted or unsubstitutedalkenyl, substituted or unsubstituted alkynyl, substituted orunsubstituted aryl, or substituted or unsubstituted heteroaryl, whereinR^(C) is hydrogen or substituted or unsubstituted alkyl, or R^(2A) andR^(2B), together with the carbon atom to which they are attached form anoxo group, wherein R^(2A) and R^(2B) are not both simultaneouslyhydrogen; R³ is substituted or unsubstituted alkyl, substituted orunsubstituted alkenyl, substituted or unsubstituted alkynyl, or —OR^(A),wherein R^(A) is substituted or unsubstituted alkyl; R⁴ is absent orhydrogen; and

represents a single or double bond, wherein when one of

is a double bond, the other

is a single bond; when both of

are single bonds, then R⁴ is hydrogen; and when one of the

is a double bond, R⁴ is absent, or a pharmaceutical compositioncomprising said compound of Formula (B) or pharmaceutically acceptablesalt thereof, and a pharmaceutically acceptable carrier. 78.-174.(canceled)
 175. The method according to any one of claims 68, 70 or 77,wherein n is
 1. 176. The method according to any one of claims 68, 70 or77, where n is
 2. 177. The method according to any one of claims 68, 70or 77, wherein each of R^(1A) and R^(1B) is independently unsubstitutedor substituted alkyl.
 178. The method according to any one of claims 68,70 or 77, wherein each of R^(1A) and R^(1B) is independently selectedfrom the group consisting of haloalkyl, alkoxyalkyl, —CH₃, CH₂CH₃,—CH(CH₃)₂, —CF₃ and —CH₂OCH₃.
 179. The method according to any one ofclaims 68, 70 or 77, wherein R^(1A) and R^(1B), together with the carbonatom to which they are attached form a 3-8 membered ring.
 180. Themethod according to any one of claims 68, 70 or 77, wherein R^(1A) ishydrogen and R^(1B) is alkyl, carbocyclyl, heterocyclyl, aryl, orheteroaryl.
 181. The method according to any one of claims 68, 70 or 77,wherein each of R^(2A) and R^(2B) is independently substituted orunsubstituted alkyl.
 182. The method according to any one of claims 68,70 or 77, wherein R³ is substituted or unsubstituted alkyl.
 183. Themethod according to any one the claims 68, 70 or 77, wherein thecompound is selected from the group consisting of


184. The method according to any one of claims 68, 70 or 77, wherein thecompound is a pharmaceutically acceptable salt of a compound selectedfrom the group consisting of: